EP0325129A2 - Disubstituted pyridines - Google Patents

Abstract

Disubstituted pyridines can be prepared by reduction of pyridines which are substituted by keto radicals, and appropriate further processing. The novel disubstituted pyridines can be used as active compounds in medicaments.

Description

The invention relates to disubstituted pyridines, intermediates for their preparation, their preparation and their use in medicaments.

It is known that lactone derivatives isolated from fungal cultures are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase) [Mevinolin, EP-A 22 478; US 4,231,938]. In addition, certain indole derivatives or pyrazole derivatives are inhibitors of HMG-CoA reductase [EP-A 1 114 027; US 4,613,610].

in weicher

• R' - Heteroaryl bedeutet, das bis zu 3-fach gleich oder verschieden durch Halogen, Alkyl, Alkoxy, Alkylthio, Alkylsulfonyl, Aryl, Aryloxy, Arylthio, Arylsulfonyl, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Alkoxycarbonyl oder durch eine Gruppe der Formel -NR⁴R⁵ substituiert sein kann, worin
• R⁴, R^{S -} gleich oder verschieden sind und Alkyl, Aryl, Aralkyl, Acyl, Alkylsulfonyl oder Arylsulfonyl bedeuten, oder
• - Aryl bedeutet, das bis zu 5-fach gleich oder verschieden substituiert sein kann durch Alkyl, Alkoxy, Alkylthio, Alkylsulfonyl, Aryl, Aryloxy, Arylthio, Arylsulfonyl, Aralkyl, Aralkoxy, Aralkylthio, Aralkylsulfonyl, Halogen, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Alkoxycarbonyl, Sulfamoyl, Dialkylsulfamoyl, Carbamoyl, Dialkylcarbamoyl oder durch eine Gruppe der Formel -NR⁴R⁵, worin
• R⁴ und R⁵ die oben angegebene Bedeutung haben,
• R^{2 -} Cycloalkyl bedeutet, oder
• - Alkyl bedeutet, das substituiert sein kann durch Halogen, Cyano, Alkoxy, Alkylthio, Alkylsulfonyl, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Trifluormethylsulfonyl, Alkoxycarbonyl, Acyl oder durch eine Gruppe der Formel -NR⁴R⁵, worin
• R⁴, R^{s -} gleich oder verschieden sind und Alkyl, Aryl, Aralkyl, Acyl, Alkylsulfonyl oder Arylsulfonyl bedeuten,
• oder durch Carbamoyl, Dialkylcarbamoyl, Sulfamoyl, Dialkylsulfamoyl, Heteroaryl, Aryl, Aryloxy, Arylthio, Arylsulfonyl, Aralkoxy, Aralkylthio oder Aralkylsulfonyl, wobei die Heteroaryl- und Arylreste der letztgenannten Substituenten bis zu 3-fach gleich oder verschieden durch Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Alkyl, Alkoxy, Alkylthio oder Alkylsulfonyl substituiert sein können,
• R^{3 -} Wasserstoff bedeutet, oder
• - Cycloalkyl bedeutet, oder
• - Alkyl bedeutet, das substituiert sein kann durch Halogen, Cyano, Alkoxy, Alkylthio, Alkylsulfonyl, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Trifluormethylsulfonyl, Alkoxycarbonyl, Acyl oder durch eine Gruppe der Formel -NR4.RS, worin
• R⁴, R⁵ die oben angegebene Bedeutung haben,
• oder durch Carbamoyl, Dialkylcarbamoyl, Sulfamoyl, Dialkylsulfamoyl, Heteroaryl, Aryl, Aryloxy, Arylthio, Arylsulfonyl, Aralkoxy, Aralkylthio oder Aralkylsulfonyl, wobei die Heteroaryl- und Arylreste bis zu 3-fach gleich oder verschieden durch Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Alkyl, Alkoxy, Alkylthio oder Alkyisulfonyl substituiert sein können, oder
• - Heteroaryl bedeutet, das bis zu 3-fach gleich oder verschieden durch Halogen, Alkyl, Alkoxy, Alkylthio, Alkylsulfonyl, Aryl, Aryloxy, Arylthio, Arylsulfonyl, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Alkoxycarbonyl oder durch eine Gruppe der Formel -NR⁴R⁵ substituiert sein kann, worin
• R⁴ und R⁵ die oben angegebene Bedeutung haben, oder
• - Aryl bedeutet, das bis zu 5-fach gleich oder verschieden substituiert sein kann durch Alkyl, Alkoxy, Alkylthio, Alkylsulfonyl, Aryl, Aryloxy, Arylthio, Arylsulfonyl, Aralkyl, Aralkoxy, Aralkylthio, Aralkylsulfonyl, Halogen, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Alkoxycarbonyl, Sulfamoyl, Dialkylsulfamoyl, Carbamoyl, Dialkylcarbamoyl oder durch eine Gruppe der Formel -NR^¢R^S, worin
• R⁴ und R⁵ die oben angegebene Bedeutung haben,
• X - eine Gruppe der Formel -CH₂-CH₂- oder -CH = CH- bedeutet, und
• A - eine Gruppe der Formel
  
  bedeutet, worin
• R^{6 -} für Wasserstoff oder Alkyl steht, und
• R^{7 -} für Wasserstoff steht oder
• - für Alkyl, Aryl oder Aralkyl steht oder
• - für ein Kation steht, gefunden.

Disubstituted pyridines of the general formula (I)

in softer

• R '- Heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ may be substituted, wherein
• R ⁴ , R ^{S - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or
• - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ , wherein
• R ⁴ and R ^{5 have} the meaning given above,
• R ² denotes cycloalkyl, or
• - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁴ R ⁵ , in which
• R ⁴ , R ^{s are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl,
• or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, the heteroaryl and aryl radicals of the latter substituents being up to 3 times the same, different by tri-fluoro, identical or different by Trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl can be substituted,
• R ^{3 represents} hydrogen, or
• - Cycloalkyl means or
• - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR4.RS, wherein
• R ⁴ , R ^{5 have} the meaning given above,
• or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, wherein the heteroaryl and aryl groups of up to 3 times by identical or different halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl , Alkoxy, alkylthio or alkylsulfonyl may be substituted, or
• - Heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ can be substituted wherein
• R ⁴ and R ^{5 have} the meaning given above, or
• - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ^¢ R ^S , wherein
• R ⁴ and R ^{5 have} the meaning given above,
• X is a group of the formula -CH ₂ -CH ₂ - or -CH = CH-, and
• A - a group of the formula
  
  means what
• R ^{6 - represents} hydrogen or alkyl, and
• R ^{7 - represents} hydrogen or
• - represents alkyl, aryl or aralkyl or
• - stands for a cation, found.

Surprisingly, the disubstituted pyridines according to the invention show a superior inhibitory effect on the HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl coenzyme A reductase).

Cycloalkyl generally represents a cyclic hydrocarbon radical with 3 to 8 carbon atoms. The cyclopropyl, cyclopentane and cyclohexane rings are preferred. Examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Alkyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Lower alkyl having 1 to about 6 carbon atoms is preferred. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.

Alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via an oxygen atom. Lower alkoxy having 1 to about 6 carbon atoms is preferred. An alkoxy radical having 1 to 4 carbon atoms is particularly preferred. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.

Alkylthio generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via a sulfur atom. Lower alkylthio having 1 to about 6 carbon atoms is preferred. An alkylthio radical having 1 to 4 carbon atoms is particularly preferred. Examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio, hexylthio, isohexylthio, heptylthio, isoheptylthio, octylthio or isooctylthio.

Alkylsulfonyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms, which is bonded via an S0 ₂ group. Lower alkylsulfonyl having 1 to about 6 carbon atoms is preferred. Examples include: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, isohexylsulfonyl.

Sulfamoyl (aminosulfonyl) stands for the group -S0 ₂ -NH2.

Aryl generally represents an aromatic radical having 6 to about 12 carbon atoms. Preferred aryl radicals are phenyl, naphthyl and biphenyl.

Aryloxy generally represents an aromatic radical having 6 to about 12 carbon atoms, which is bonded via an oxygen atom. Preferred aryloxy radicals are phenoxy or naphthyloxy.

Arylthio generally represents an aromatic radical having 6 to about 12 carbon atoms, to which a sulfur atom is attached. Preferred arylthio radicals are phenylthio or naphthylthio.

Arylsulfonyl generally represents an aromatic radical having 6 to about 12 carbon atoms, which is bonded via an S0 ₂ group. Examples include: phenylsulfonyl, naphthylsulfonyl and biphenylsulfonyl.

Aralkyl generally represents an aryl radical having 7 to 14 carbon atoms bonded via an alkylene chain. Aralkyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. The following aralkyl radicals may be mentioned, for example: benzyl, naphthylmethyl, phenethyl and phenylpropyl.

Aralkoxy generally represents an aralkyl radical having 7 to 14 carbon atoms, the alkylene chain being bonded via an oxygen atom. Aralkoxy radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 1'2 carbon atoms in the aromatic part are preferred. The following aralkoxy radicals may be mentioned, for example: benzyloxy, naphthylmethoxy, phenethoxy and phenylpropoxy.

Aralkylthio generally represents an aralkyl radical having 7 to about 14 carbon atoms, the alkyl chain being bonded via a sulfur atom. Aralkylthio radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. Examples include the following aralkylthio radicals: benzylthio, naphthylmethylthio, phenethylthio and phenylpropylthio.

Aralkylsulfonyl generally represents an aralkyl radical having 7 to about 14 carbon atoms, the alkyl radicals being bonded via an SO 2 chain. Aralkylsulfonyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. Examples include the following aralkylsulfonyl radicals: benzylsulfonyl, naphthylmethylsulfonyl, phenethylsulfonyl and phenylpropylsulfonyl.

• ^{- C} _II -OAlky_l 0 dargestellt werden. Alkyl steht hierbei für einen geradkettigen oder verzweigten Kohlenwasserstoffrest mit 1 bis 12 Kohlenstoffatomen. Bevorzugt wird Niederalkoxycarbonyl mit 1 bis etwa 6 Kohlenstoffatomen im Alkylteil. Insbesondere bevorzugt wird ein Alkoxycarbonyl mit 1 bis 4 Kohlenstoffatomen im Alkylteil. Beispielsweise seien die folgenden Alkoxycarbonylreste genannt: Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycarbonyl, Butoxycarbonyl oder Isobutoxycarbonyl.

Alkoxycarbonyl can, for example, by the formula

• ^{- C} _II -OAlky _l 0 are shown. Alkyl here is a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Lower alkoxycarbonyl having 1 to about 6 carbon atoms in the alkyl part is preferred. An alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part is particularly preferred. Examples include the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Acyl generally represents phenyl or straight-chain or branched lower alkyl having 1 to about 6 carbon atoms which are bonded via a carbonyl group. Phenyl and alkyl radicals having up to 4 carbon atoms are preferred. Examples include: benzoyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.

Halogen generally represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. Halogen is particularly preferably fluorine or chlorine.

Heteroaryl generally represents a 5- to 6-membered aromatic ring which can contain oxygen, sulfur and / or nitrogen as heteroatoms and to which further aromatic rings can be fused. 5- and 6-membered aromatic rings are preferred which contain an oxygen, a sulfur and or up to 2 nitrogen atoms and which are optionally benzo-condensed. Particularly preferred heteroaryl residues are: thienyl, furyl, pyrolyl, pyrazolyl, pyridyl, pyrimidyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, phthalazinyl, cinnolyl, thiazolyl, benzothiazolyl, isothiazoiyl, oxazylyl , Indolyl, and isoindolyl.

in weicher

• R', R², R³, X und A die oben angegebene Bedeutung haben.

In the context of the present invention, the disubstituted pyridines (Ia) correspond to the general formula

in softer

• R ', R ² , R ³ , X and A have the meaning given above.

in welcher

• R¹, R², R³, X und A die oben angegebene Bedeutung haben.

In the context of the present invention, the disubstituted pyridines (Ib) correspond to the general formula

in which

• R ¹ , R ² , R ³ , X and A have the meaning given above.

In the context of the general formula (I), compounds having the general formulas (Ia) and (Ib) are preferred.

in welchen

• R' - Thienyl, Furyl, Thiazolyl, Isothiazolyl, Oxazolyl, Isoxazolyl, Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Indolyl, Isoindolyl, Chinolyl, Isochinolyl, Phthalazinyl, Chinoxalinyl, Chinazolinyl, Cinnolinyl, Benzothiazolyl, Benzoxazolyl oder Benzimidazolyl bedeutet, das bis zu 2-fach gleich oder verschieden substituiert sein kann durch Fluor, Chlor, Brom, Niederalkyl, Niederalkoxy, Phenyl, Phenoxy, Trifluormethyl, Trifluormethoxy oder Niederalkoxycarbonyl, oder
• - Phenyl oder Naphthyl bedeutet, das bis zu 4-fach gleich oder verschieden substituiert sein kann durch Niederalkyl, Niederalkoxy, Niederalkylthio, Niederalkylsulfonyl, Phenyl, Phenyloxy, Phenylthio, Phenylsulfonyl, Benzyl, Benzyloxy, Benzylthio, Benzylsulfonyl, Phenethyl, Phenylethoxy, Phenylethylthio, Phenylethylsulfonyl, Fluor, Chlor, Brom, Cyano, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Niederalkoxycarbonyl oder durch eine Gruppe der Formel -NR⁴R^s, wobei
• R⁴ und R⁵ gleich oder verschieden sind und Niederalkyl, Phenyl, Benzyl, Acetyl, Benzoyl, Phenylsulfonyl oder Niederalkylsulfonyl bedeuten,
• R^{2 -} Cyclopropyl, Cyclopentyl oder Cyclohexyl bedeutet, oder
• - Niederalkyl bedeutet, das substituiert sein kann durch Fluor, Chlor, Brom, Cyano, Niederalkoxy, Niederalkylthio, Niederalkylsulfonyl, Phenyl, Trifluormethyl, Trifluormethoxy, Trifluormethylsulfonyl, Niederalkoxycarbonyl, Benzoyl, Niederalkylcarbonyl, durch eine Gruppe der Formel -NR"R⁵, worin
• R⁴ und R⁵ die oben angegebene Bedeutung haben, oder durch Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Chinolyl, Isochinolyl, Pyrrolyl, Indolyl, Thienyl, Furyl, Imidazolyl, Oxazolyl, Thiazolyl, Phenyl, Phenoxy, Phenylthio, Phenylsulfonyl, Benzyloxy, Benzylthio, Benzylsulfonyl, Phenylethoxy, Phenylethylthio oder Phenylethylsulfonyl, wobei die genannten Heteroaryl- und Arylreste bis zu 2-fach gleich oder verschieden durch Fluor, Chlor, Brom, Niederalkyl, Niederalkoxy, Trifluormethyl, oder Trifluormethoxy substituiert sein können, R^{3 -} Wasserstoff, oder
• - Cyclopropyl, Cyclopentyl oder Cyclohexyl bedeutet, oder
• - Niederalkyl bedeutet, das substituiert sein kann durch Fluor, Chlor, Brom, Cyano, Niederalkoxy, Nie deralkylthio, Niederalkylsulfonyl, Trifluormethyl, Trifluormethoxy, Trifluormethylsulfonyl, Niederalkoxycarbonyl, Benzoyl, Niederalkylcarbonyl, durch ein Gruppe der Formel -NR₄Rs, worin
• R⁵ und R⁶ die oben angegebene Bedeutung haben,
• oder durch Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Chinolyl, Isochinolyl, Pyrrolyl, Indolyl, Thienyl, Furyl, Imidazolyl, Oxazolyl, Thiazolyl, Phenyl, Phenoxy, Phenylthio, Phenylsulfonyl, Benzyloxy, Benzylthio, Benzylsulfonyl, Phenylethoxy, Phenylethylthio oder Phenylethylsulfonyl, wobei die genannten Heteroaryl-und Arylreste bis zu 2-fach gleich oder verschieden durch Fluor, Chlor, Brom, Niederalkyl, Niederalkoxy, Trifluormethyl, oder Trifluormethoxy substituiert sein können,
• - Thienyl, Furyl, Thiazolyl, Isothiazolyl, Oxazolyl, Isoxazolyl, Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Indolyl. Isoindolyl, Chinolyl, Isochinolyl, Phthalazinyl, Chinoxalinyl, Chinazolinyl, Cinnolinyl, Benzothiazolyl, Benzoxazolyl oder Benzimidazolyl bedeutet, das bis zu 2-fach gleich oder verschieden substituiert sein kann durch Fluor, Chlor, Brom, Niederalkyl, Niederalkoxy, Phenyl, Phenoxy, Trifluormethyl, Trifluormethoxy oder Niederalkoxycarbonyl, oder
• - Phenyl oder Naphthyl bedeutet, das bis zu 4-fach gleich oder verschieden substituiert sein kann durch Niederalkyl, Niederalkoxy, Niederalkylthio, Niederalkylsulfonyl, Phenyl, Phenyloxy, Phenylthio, Phenylsulfonyi, Benzyl, Benzyloxy, Benzylthio, Benzylsulfonyl, Phenethyl, Phenylethoxy, Phenylethylthio, Phenylethylsulfonyl. Fluor, Chlor, Brom, Cyano, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Niederalkoxycarbonyl oder durch eine Gruppe der Formel -NR⁵R⁶, wobei
• R⁵ und R⁶ die oben angegebene Bedeutung haben,
• X - eine Gruppe der Formel -CH = CH- bedeutet und
• A - eine Gruppe der Formel
  
  bedeutet, worin
• R^{6 -} Wasserstoff oder Niederalkyl bedeutet, und
• R^{7 -} Niederalkyl, Phenyl oder Benzyl bedeutet, oder - ein physiologisch verträgliches Kation bedeutet.

Compounds of the general formula (Ia) and (Ib) are preferred

in which

• R '- thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which up to 2 may be substituted in the same or different ways by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or
• - Phenyl or naphthyl, which can be substituted up to 4 times in the same or different way by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylsulfonyl, phenyl , Fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR ⁴ R ^s , where
• R ⁴ and R ^{5 are} identical or different and are lower alkyl, phenyl, benzyl, acetyl, benzoyl, phenylsulfonyl or lower alkylsulfonyl,
• R ² denotes cyclopropyl, cyclopentyl or cyclohexyl, or
• - Lower alkyl means that can be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by a group of the formula -NR "R ⁵ , in which
• R ⁴ and R ^{5 have} the meaning given above, or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio , Benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, where the heteroaryl and aryl radicals mentioned can be substituted up to 2 times identically or differently by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl, or trifluoromethoxy, R ^{3 -} hydrogen, or
• - Cyclopropyl, cyclopentyl or cyclohexyl, or
• - Lower alkyl means that can be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, Nie deralkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by a group of the formula -NR ₄ Rs, wherein
• R ⁵ and R ^{6 have} the meaning given above,
• or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethysylonethyl, phenylethysulfonyl, phenyl The heteroaryl and aryl radicals mentioned can be substituted up to twice in the same or different manner by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy,
• - thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl. Isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which can be substituted up to 2 times by the same or different substituents by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, Trifluoromethoxy or lower alkoxycarbonyl, or
• - Phenyl or naphthyl, which can be substituted up to 4 times in the same or different manner by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyi, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylsulfonyl, phenyl . Fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or through a group of the formula -NR ⁵ R ⁶ , where
• R ⁵ and R ^{6 have} the meaning given above,
• X is a group of the formula -CH = CH- and
• A - a group of the formula
  
  means what
• R ^{6 represents} hydrogen or lower alkyl, and
• R ⁷ means lower alkyl, phenyl or benzyl, or means a physiologically compatible cation.

• R' - Pyridyl, Pyrimidyl, Chinolyl oder Isochinolyl bedeutet, das durch Fluor, Chlor, Methyl, Methoxy oder Trifluormethyl substituiert sein kann, oder
• - Phenyl bedeutet, das bis zu 3-fach gleich oder verschieden substituiert sein kann durch Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, Isobutoxy, tert.Butoxy, Methylthio, Ethylthio, Propylthio, Isopropylthio, Methylsulfonyl, Ethylsulfonyl, Propylsulfonyl, Isopropylsulfonyl, Phenyl, Phenoxy, Benzyl, Benzyloxy, Fluor, Chlor, Brom, Cyano, Trifluormethyl, Trifluormethoxy, Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl oder tert.Butoxycarbonyl,
• R^{2 -} Cyclopropyl, Cyclopentyl oder Cyclohexyl bedeutet, oder
• - Methyl, Ethyl, Propyl, Isopropyl, Butyl, sec.-Butyl oder tert.Butyl bedeutet, das substituiert sein kann durch Fluor, Chlor, Brom, Cyano, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, sec.Butoxy, tert.Butoxy, Methylthio, Ethylthio, Propylthio, Isopropylthio, Methylsulfonyl, Ethylsulfonyl, Propylsulfonyl, Isopropylsulfonyl, Trifluormethyl, Trifluormethoxy, Methoxycarbonyl, Ethoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl, tert.-Butoxycarbonyl, Benzoyl, Acetyl, Pyridyl, Pyrimidyl, Thienyl, Furyl, Phenyl, Phenoxy, Phenylthio, Phenylsulfonyl. Benzyloxy, Benzylthio oder Benzylsulfonyl,
• R^{3 -} Wasserstoff, Cyclopropyl, Cyclopentyl oder Cyclohexyl bedeutet, oder
• - Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Pentyl, Isopentyl, Hexyl oder Isohexyl bedeutet, das substituiert sein kann durch Fluor, Chlor, Brom, Cyano, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, tsobutoxy, tert.Butoxy, Methylthio, Ethylthio, Propylthio, Isopropylthio, Butylthio, Isobutylthio, tert.Butylthio, Methyisulfonyl, Ethylsulfonyl, Propylsulfonyl, Isopropylsulfonyl, Butylsulfonyl, Isobutylsulfonyl, tert.Butylsulfonyl, Trifluormethyl, Trifluormethoxy, Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl, tert.Butoxycarbonyl, Benzoyl, Acetyl, Ethylcarbonyl, oder durch eine Gruppe -NR⁴R⁵, wobei
• R⁴ und R⁵ gleich oder verschieden sind und Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Phenyl, Benzyl, Acetyl, Methylsulfonyl, Ethylsulfonyl, Propylsulfonyl, Isopropylsulfonyl oder Phenylsulfonyl bedeuten,
• oder durch Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Chinolyl, Isochinolyl, Thienyl, Furyl, Phenyl, Phenoxy, Phenylthio, Phenylsulfonyl, Benzyloxy, Benzylthio oder Benzylsulfonyl, wobei die genannten Heteroaryl-und Arylreste durch Fluor, Chlor, Methyl, Ethyl, Propyl, Isopropyl, Isobutyl, tert. Butyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, Isobutoxy, tert.-Butoxy, Trifluormethyl oder Trifluormethoxy substituiert sein können, oder
• - Thienyl, Furyl, Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Oxazolyl, Isooxazolyl, Imidazolyl, Pyrazolyl, Thiazolyl, Isothiazolyl, Chinolyl, Isochinolyl, Benzoxazolyl, Benzimidazolyl oder Benzthiazolyl bedeutet, wobei die genannten Reste durch Fluor, Chlor, Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, Isobutoxy, tert.Butoxy, Phenyl, Phenoxy, Trifluormethyl, Trifluormethoxy, Methoxycarbonyl, Ethoxycarbonyl, Isopropoxycarbonyl, Propoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl oder tert.Butoxycarbonyl substituiert sein können, oder
• - Phenyl bedeutet, das bis zu 3-fach gleich oder ver schieden durch Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Pentyl, Isopentyl, Hexyl, Isohexyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, Isobutoxy, tert.-Butoxy, Methylthio, Ethylthio, Propylthio, Isopropylthio, Butylthio, Isobutylthio, tert.Butylthio, Methylsulfonyl, Ethylsulfonyl, Propylsulfonyl, Isopropylsulfonyl, Butylsulfonyl, Isobutylsulfonyl, tert.Butylsulfonyl, Phenyl, Phenoxy, Phenylthio, Phenylsulfonyl, Benzyl, Benzyloxy, Benzylthio, Benzylsulfonyl, Fluor, Chlor, Brom, Cyano, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl, tert.Butoxycarbonyl oder durch eine Gruppe -NR⁴R⁵ substituiert sein kann, wobei
• R4- und R⁵ die oben angegebene Bedeutung haben, X - eine Gruppe der Formel -CH=CH- bedeutet und
• A - eine Gruppe der Formel
  
  bedeutet, worin
• R^{6 -} Wasserstoff, Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl oder tert.Butyl bedeutet und
• R^{7 -} Wasserstoff, Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl oder Benzyl bedeutet, oder - ein Natrium-, Kalium-, Calcium- oder Magnesium- oder Ammoniumion bedeutet.

Compounds of the general formulas (Ia) and (Ib) in which are particularly preferred

• R 'is pyridyl, pyrimidyl, quinolyl or isoquinolyl, which can be substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or
• - Phenyl means that up to 3 times the same or different substitution can be substituted by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio , Ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, butoxycarbonyl, butoxy ,
• R ² denotes cyclopropyl, cyclopentyl or cyclohexyl, or
• - Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, which can be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert. Butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.-butoxycarbonyl, pyridyl, pyridyl, pyridylyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl , Phenylthio, phenylsulfonyl. Benzyloxy, benzylthio or benzylsulfonyl,
• R ^{3 is} hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or
• - Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl, which can be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tsobutoxy , tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tri-butylifoxycarbonyl, methylbutylifoxycarbonyl, methylbutylifoxycarbonyl, methylbutylifoxycarbonyl, methylbutylifoxycarbonyl , Isobutoxycarbonyl, tert.butoxycarbonyl, benzoyl, acetyl, ethylcarbonyl, or by a group -NR ⁴ R ⁵ , where
• R ⁴ and R ^{5 are the} same or different and are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, phenyl, benzyl, acetyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or phenylsulfonyl,
• or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, furyl, phenyl, phenoxy, Phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, the heteroaryl and aryl radicals mentioned being tert-substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, isobutyl. Butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, trifluoromethyl or trifluoromethoxy may be substituted, or
• - Thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isooxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzothiazolyl, with the radicals being methyl, eth, by fluorine , Isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert may be substituted, or
• - Phenyl means up to 3 times the same or different by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.Butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert.Butylsulfonyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyl, benzyloxy, Benzylthio, benzylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl or by a group -NR ⁴ R ⁵ , where may be substituted
• R4- and R ^{5 have} the meaning given above, X - is a group of the formula -CH = CH- and
• A - a group of the formula
  
  means what
• R ^{6 is} hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl and
• R ^{7 means} hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl, or - means a sodium, potassium, calcium or magnesium or ammonium ion.

• R' - Phenyl bedeutet, das bis zu 2-fach gleich oder verschieden durch Methyl, Ethyl, Propyl, Isopropyl, Phenoxy und/oder Fluor substituiert sein kann,
• R^{2 -} für Cyclopropyl oder Cyclohexyl steht oder Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl oder tert.Butyl bedeutet, das durch Fluor, Chlor, Methoxy, Phenyl oder Phenoxy substituiert sein kann,
• R^{3 -} Wasserstoff, Cyclopropyl, Cyclopentyl oder Cyclohexyl oder Phenyl bedeutet, oder
• - Methyl, Ethyl, Propyl, Isopropyl, Butyl oder Benzyl bedeutet,
• X - eine Gruppe der Formel
  
  und
• A - eine Gruppe der Formel
  
  bedeutet, worin
• R^{6 -} Wasserstoff bedeutet und
• R^{7 -} Wasserstoff, Methyl oder Ethyl bedeutet, oder - ein Natrium- oder Kaliumkation bedeutet.

Compounds of the general formulas (Ia) and (Ib) in which are very particularly preferred

• R '- phenyl which can be substituted up to two times, identically or differently, by methyl, ethyl, propyl, isopropyl, phenoxy and / or fluorine,
• R ^{2 - stands} for cyclopropyl or cyclohexyl or means methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, which can be substituted by fluorine, chlorine, methoxy, phenyl or phenoxy,
• R ^{3 is} hydrogen, cyclopropyl, cyclopentyl or cyclohexyl or phenyl, or
• Means methyl, ethyl, propyl, isopropyl, butyl or benzyl,
• X - a group of the formula
  
  and
• A - a group of the formula
  
  means wherein
• R ⁶ means hydrogen and
• R ^{7 means} hydrogen, methyl or ethyl, or means a sodium or potassium cation.

The disubstituted pyridines of the general formula (I) according to the invention have several asymmetric carbon atoms and can therefore exist in various stereochemical forms. Both the individual isomers and their mixtures are the subject of the invention.

• a) Steht die Gruppe -X- für eine Gruppe der Formel -CH=CH- , so können die erfindungsgemäßen Verbindungen in zwei stereoisomeren Formen existieren, die an der Doppelbindung E-konfiguriert (II) oder Z-konfiguriert (III) sein können:
  
  
  worin R¹. R². R³, X und A die oben angegebene Bedeutung haben. Bevorzugt sind diejenigen Verbindungen der allgemeinen Formel (I) die E-konfiguriert sind (11).
• b) Steht der Rest -A für eine Gruppe der Formel
  
  so besitzen die Verbindungen der allgemeinen Formel (I) mindestens zwei asymmetrische Kohlenstoffatome. nämlich die beiden Kohlenstoffatome an denen die Hydroxygruppen gebunden sind. Je nach der relativen Stellung dieser Hydroxygruppen zueinander, können die erfindungsgemäßen Verbindungen in der erythro-Konfiguration (IV) oder in der threo-Konfiguration (V) vorliegen.
  
  
  Sowohl von den Verbindungen in Erythro- als auch in Threo-Konfiguration existieren wiederum jeweils zwei Enantiomere, nämlich 3R,5S-Isomeres bzw. 3S,5R-Isomeres (Erythro-Form) sowie 3R,5R-Isomeres und 3S,5S-Isomeres (Threo-Form). Bevorzugt sind hierbei die Erythro-konfigurierten Isomeren, besonders bevorzugt das 3R,5S-Isomere sowie das 3R,5S-3S,5R-Racemat.
• c) Steht der Rest -A für eine Gruppe der Formel
  
  so besitzen die disubstituierten Pyridine mindestens zwei asymmetrische Kohlenstoffatome, nämlich das Kohlenstoffatom an dem die Hydroxygruppe gebunden ist, und das Kohlenstoffatom an welchem der Rest der Formel
  
  gebunden ist. Je nach der Stellung der Hydroxygruppe zur freien Valenz am Lactonring können die disubstituierten Pyridine als cis-Lactone (VI) oder als trans-Lactone (VII) vorliegen.
  
  

Depending on the meaning of the groups X and the radicals A, different stereoisomers result, which should be explained in more detail below:

• a) If the group -X- stands for a group of the formula -CH = CH-, the compounds according to the invention can exist in two stereoisomeric forms which can be E-configured (II) or Z-configured (III) on the double bond:
  
  
  where R ¹ . R ² . R ³ , X and A have the meaning given above. Preferred compounds of the general formula (I) are E-configured (11).
• b) The radical -A stands for a group of the formula
  
  the compounds of the general formula (I) have at least two asymmetric carbon atoms. namely the two carbon atoms to which the hydroxy groups are attached. Depending on the relative position of these hydroxyl groups to one another, the compounds according to the invention can be in the erythro configuration (IV) or in the threo configuration (V).
  
  
  Both of the compounds in the erythro and in the threo configuration each have two enantiomers, namely 3R, 5S isomer and 3S, 5R isomer (erythro form) as well as 3R, 5R isomer and 3S, 5S isomer ( Threo shape). The erythro-configured isomers are preferred, particularly preferably the 3R, 5S isomer and the 3R, 5S-3S, 5R racemate.
• c) The radical -A stands for a group of the formula
  
  so the disubstituted pyridines have at least two asymmetric carbon atoms, namely the carbon atom to which the hydroxy group is attached and the carbon atom to which the rest of the formula
  
  is bound. Depending on the position of the hydroxyl group in relation to the free valence on the lactone ring, the disubstituted pyridines can be present as cis-lactones (VI) or as trans-lactones (VII).
  
  

Both the cis-lactone and the trans-lactone each exist. two isomers namely the 4R, 6R isomer or the 4S, 6S isomer (cis-lactone), and the 4R, 6S isomer or 4S, 6R isomer (trans-lactone). Preferred isomers are the trans lactones. The 4R, 6S isomer (trans) and the 4R, 6S-4S, 6R racemate are particularly preferred.

The following isomeric forms of the substituted pyridines may be mentioned, for example:

In addition, there are further possibilities for isomer formation, since the disubstituted pyridines according to the invention are substituted by two groups of the formula -X-A. The same applies to the second group -X-A in the molecule. The invention also relates to all stereoisomers which arise from the second group of the formula -X-A, in particular in connection with the first group -X-A.

in welcher

• R', R², R³, X und A die oben angegebene Bedeutung haben, gefunden,
• das dadurch gekennzeichnet ist, daß man
• Ketone der allgemeinen Formel (VIII)
  
  in welcher
• R¹, R² und R³ die oben angegebene Bedeutung haben, und
• _R ⁸ - für Alkyl steht, reduziert,
• im Fall der Herstellung der Säuren die Ester verseift,
• im Fall der Herstellung der Lactone die Carbonsäuren cyclisiert,
• im Fall der Herstellung der Salze entweder die Ester oder die Lactone verseift,
• im Fall der Herstellung der Ethylenverbindungen (X = -CH₂-CH₂-) die Ethenverbindungen (X = -CH=CH-) nach üblichen Methoden hydriert,
• und gegebenenfalls Isomeren trennt.

In addition, a process for the preparation of the disubstituted pyridines of the general formula (I)

in which

• R ', R ² , R ³ , X and A have the meaning given above, found,
• which is characterized in that one
• Ketones of the general formula (VIII)
  
  in which
• R ¹ , R ² and R ^{3 have} the meaning given above, and
• _R ⁸ - represents alkyl, reduced,
• in the case of production of the acids, the esters are saponified,
• in the case of the production of the lactones, the carboxylic acids are cyclized,
• in the case of the preparation of the salts, either the esters or the lactones are saponified,
• in the case of the production of the ethylene compounds (X = -CH ₂ -CH ₂ -) the ethene compounds (X = -CH = CH-) are hydrogenated by customary methods,
• and optionally separates isomers.

The process according to the invention can be illustrated by the following formula:

The reduction can be carried out using the customary reducing agents, preferably those which are suitable for the reduction of ketones to hydroxy compounds. Reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane, is particularly suitable. The reduction is preferably carried out with complex metal hydrides such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkyl hydridoborates, sodium trialkyl hydridoborates, sodium cyano-trihydridoborate or lithium aluminum hydride. The reduction with sodium borohydride is very particularly preferably carried out in the presence of triethylborane.

The usual organic solvents which do not change under the reaction conditions are suitable as solvents. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, or hydrocarbons such as benzene, toluene or xylene. It is also possible to use mixtures of the solvents mentioned.

The reduction of the ketone group to the hydroxyl group is particularly preferably carried out under conditions in which the other functional groups such as the alkoxycarbonyl group are not changed. The use of sodium borohydride as reduc is particularly suitable for this tion agent, in the presence of triethylborane in inert solvents such as preferably ethers.

The reduction is generally carried out in a temperature range from -80 ° C. to + 30 ° C., preferably from -78 ° C. to 0 ° C.

The process according to the invention is generally carried out at normal pressure. However, it is also possible to carry out the process under negative pressure or under positive pressure (e.g. in a range from 0.5 to 5 bar).

In general, the reducing agent is used in an amount of 1 to 2 mol, preferably 1 to 1.5 mol, based on 1 mol of the keto compound.

Under the reaction conditions given above, the carbonyl group is generally reduced to the hydroxyl group without the double bond being reduced to the single bond.

To prepare compounds of the general formula (I) in which X represents an ethylene grouping, the reduction of the ketones (VIII) can be carried out under conditions under which both the carbonyl group and the double bond are reduced.

In addition, it is also possible to carry out the reduction of the carbonyl group and the reduction of the double bond in two separate steps.

in welcher

• R¹, R², R³, R⁶ und X die oben angegebene Bedeutung haben.

The carboxylic acids in the context of the general formula (I) correspond to the formula (Ic)

in which

• R ¹ , R ² , R ³ , R ⁶ and X have the meaning given above.

in weicher

• R¹, _R ², R³, R⁶ und X die oben angegebene Bedeutung haben, und
• R⁸ - für Alkyl steht.

The carboxylic acid esters in the general formula (I) correspond to the formula (Id)

in softer

• R ¹ , _R ² , R ³ , R ⁶ and X have the meaning given above, and
• R ⁸ - represents alkyl.

in welcher

• R', R², R³, R⁶ und X die oben angegebene Bedeutung haben, und
• Mⁿ⊕ für ein Kation steht.

The salts of the compounds according to the invention in the context of the general formula (I) correspond to the formula (Ie)

in which

• R ', R ² , R ³ , R ⁶ and X have the meaning given above, and
• M ⁿ ⊕ stands for a cation.

in welcher

• R', R², R³, R⁶ und X die oben angegebene Bedeutung haben.

The lactones in the context of the general formula (I) correspond to the formula (If)

in which

• R ', R ² , R ³ , R ⁶ and X have the meaning given above.

To prepare the carboxylic acids of the general formula (Ic) according to the invention, the carboxylic acid esters of the general formula (Id) or the lactones of the general formula (If) are in general saponified by customary methods. The saponification is generally carried out by treating the esters or the lactones in inert solvents with customary bases, the salts of the general formula (Ie) generally being formed first, which are then treated in a second step with acid in the free acids of the general Formula (Ic) can be transferred.

The usual inorganic bases are suitable as bases for the saponification. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate, or alkali metal alcoholates such as sodium ethanolate, sodium methoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide. Sodium hydroxide or potassium hydroxide are particularly preferably used.

Suitable solvents for the saponification are water or the organic solvents customary for saponification. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used. It is also possible to use mixtures of the solvents mentioned.

The saponification is generally carried out in a temperature range from 0 ° C. to + 100 ° C., preferably from + 20 ° C. to + 80 ° C.

The saponification is generally carried out at normal pressure. However, it is also possible to work under negative pressure or overpressure (e.g. from 0.5 to 5 bar).

When saponification is carried out, the base is generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the ester or lactone. Molar amounts of the reactants are particularly preferably used.

When the reaction is carried out, the salts of the compounds (Ie) according to the invention are formed in the first step as intermediates which can be isolated. The acids (Ic) according to the invention are obtained by treating the salts (le) with customary inorganic acids. These preferably include mineral acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. In the production of the carboxylic acids (Ic), it has proven advantageous here to acidify the basic reaction mixture of the saponification in a second step without isolating the salts. The acids can then be isolated in the usual way.

To prepare the lactones of the formula (If) according to the invention, the carboxylic acids (Ic) according to the invention are generally cyclized by customary methods, for example by heating the corresponding acid in inert organic solvents, if appropriate in the presence of molecular sieve.

Suitable solvents here are hydrocarbons such as benzene, toluene, xylene, petroleum fractions, or tetralin or diglyme or triglyme. Benzene, toluene or xylene are preferably used. It is also possible to use mixtures of the solvents mentioned. Hydrocarbons, in particular toluene, are particularly preferably used in the presence of molecular sieve.

The cyclization is generally in a temperature range from -40 ° C to + 200 ° C. preferably carried out from -25 C to + 50 ° C.

The cyclization is generally carried out at normal pressure, but it is also possible to carry out the process under reduced pressure or under elevated pressure (e.g. in a range from 0.5 to 5 bar).

In addition, the cyclization is also carried out in inert organic solvents with the aid of cyclizing or water-releasing agents. Carbodiimides are preferably used as water-releasing agents. Preferred carbondiimides are N, N'-dicyclohexylcarbodiimide paratoluenesulfonate, N-cyclohexyl-N '- [2- (N "-methylmorpholinium) ethyl] carbodiimide or N- (3-dimethylamino propyl) -N'-ethylcarbodiimide hydrochloride used.

The usual organic solvents are suitable as solvents. These preferably include ethers such as diethyl ether, tetrahydrofuran or dioxane, or chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons such as benzene, toluene, xylene or petroleum fractions. Chlorinated hydrocarbons such as, for example, methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons such as benzene, toluene, xylene, or petroleum fractions are particularly preferred. Chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride are particularly preferably used.

The reaction is generally carried out in a temperature range from 0 ° C. to + 80 ° C., preferably from + 10 ° C. to + 50 ° C.

When carrying out the cyclization, it has proven to be advantageous to use the cyclization method with the aid of carbodiimides as dehydrating agents.

überführt, die anschließend wie üblich durch Chromatographie oder Kristallisation in die einzelnen Diastereomeren getrennt werden können. Anschließende Hydrolyse der reinen diastereomeren Amide nach üblichen Methoden, beispielsweise durch Behandeln der diastereomeren Amide mit anorganischen Basen wie Natriumhydroxid oder Kalium hydroxid in Wasser und/oder organischen Lösemitteln wie Alkoholen z.B. Methanol, Ethanol, Propanol oder Isopropanol, ergeben die entsprechenden enantiomerenreinen Dihydroxysäuren (lc), die wie oben beschrieben durch Cyclisierung in die enantiomerenreinen Lactone überführt werden können. Im allgemeinen gilt für die Herstellung der erfindungsgemäßen Verbindungen der allgemeinen Formel (I) in enantiomerenreiner Form, daß die Konfiguration der Endprodukt nach der oben beschriebenen Methode abhängig ist von der Konfiguration der Ausgangsstoffe.The separation of the isomers into the stereoisomerically uniform constituents is generally carried out by customary methods as described, for example, by EL Eliel, Stereochemistry of Carbon Compounds, McGraw Hili, ₁ 962. The separation of the isomers at the racemic lactone stage is preferred. The racemic mixture of the trans-lactones (VII) is particularly preferred here by treatment with either D - (+) - or L - (-) - a-methylbenzylamine by customary methods into the diastereomeric dihydroxyamides (Ig)

transferred, which can then be separated into the individual diastereomers as usual by chromatography or crystallization. Subsequent hydrolysis of the pure diastereomeric amides by customary methods, for example by treating the diastereomeric amides with inorganic bases such as sodium hydroxide or potassium hydroxide in water and / or organic solvents such as alcohols, for example methanol, ethanol, propanol or isopropanol, give the corresponding enantiomerically pure dihydroxy acids (lc) which can be converted into the enantiomerically pure lactones by cyclization as described above. In general, it applies to the preparation of the compounds of the general formula (I) according to the invention in enantiomerically pure form that the configuration of the end product by the method described above depends on the configuration of the starting materials.

The separation of isomers is to be exemplified in the following scheme:

The ketones (VIII) used as starting materials are new.

in welcher

• R¹, R² und R³ die oben angegebene Bedeutung haben und
• R⁸ - für Alkyl steht,
• gefunden, das dadurch gekennzeichnet ist, daß man Aldehyde der allgemeinen Formel (IX)
  
  in welcher
• R', R² und R³ die oben angegebene Bedeutung haben,
• in inerten Lösemitteln mit Acetessigester der allgemeinen Formel (X)
  
  in welcher
• R⁸ die oben angegebene Bedeutung hat,
• in Anwesenheit von Basen umsetzt.

A process for the preparation of the ketones of the general formula (VIII) according to the invention

in which

• R ¹ , R ² and R ^{3 have} the meaning given above and
• R ⁸ - represents alkyl,
• found, which is characterized in that aldehydes of the general formula (IX)
  
  in which
• R ', R ² and R ^{3 have} the meaning given above,
• in inert solvents with acetoacetic ester of the general formula (X)
  
  in which
• R ^{8 has} the meaning given above,
• in the presence of bases.

The method according to the invention can be illustrated, for example, by the following formula:

The bases here are the customary strongly basic compounds. These preferably include organolithium compounds such as N-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethyldisilylamide, or alkali hydrides such as sodium hydride or potassium hydride. It is also possible to use mixtures of the bases mentioned. N-Butyllithium or sodium hydride or a mixture thereof is particularly preferably used.

The usual organic solvents which do not change under the reaction conditions are suitable as solvents. These preferably include ethers such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, or hydrocarbons such as benzene, toluene, xylene, cyclohexane, hexane or oil fractions. It is also possible to use mixtures of the solvents mentioned. Ethers such as diethyl ether or tetrahydrofuran are particularly preferably used.

The reaction is generally carried out in a temperature range from -80 ° C. to + 50 ° C., preferably from -20 ° C. to + 30 ° C.

The process is generally carried out under normal pressure, but it is also possible to carry out the process under negative pressure or under positive pressure, e.g. in a range from 0.5 to 5 bar.

When carrying out the process, the acetoacetic ester is generally used in an amount of 1 to 2, preferably 1 to 1.5, mol, based on 1 mol of the aldehyde.

The acetoacetic esters of the formula (X) used as starting materials are known or can be prepared by known methods [Beilstein's Handbuch der organic Chemistry 111, 632; 438].

Examples of acetoacetic esters for the process according to the invention are: methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate, isopropyl acetoacetate.

The aldehydes of the general formula (IX) used as starting materials are new.

The preparation of the aldehydes can be exemplified by the following reaction scheme for the compounds of type (la):

In the first step [A], the dihydropyridines of the general formula (X) are oxidized in suitable solvents with suitable oxidizing agents. The dihydropyridines are preferred in chlorinated hydrocarbons such as methylene chloride, with 2,2-dichloro-5,6-dicyan-p-benzoquinone at room temperature, or with chromium trioxide in glacial acetic acid at elevated temperatures, preferably under reflux temperature, to give the pyridines of the formula (XI) oxidized. In the second step [B], the pyridines (XI) are dissolved in inert solvents such as ethers, for example diethyl ether, dioxane or tetrahydrofuran, preferably in tetrahydrofuran, with metal hydrides such as lithium aluminum hydride, sodium cyanoborohydride, diisobutyl aluminum hydride or sodium bis (2-methoxyethoxy) - dihydroaluminate, reduced in a temperature range from -80 ° C to + 40 ° C, preferably from -70 ° C to room temperature to the hydroxy compounds of the general formula (XII). In the third step [C], the hydroxy compounds (XII) are prepared by known methods using oxidizing agents such as pyridinium chlorochromate, optionally in the presence of aluminum oxide, in inert solvents such as chlorinated hydrocarbons, preferably methylene chloride, at room temperature or using trifluoroacetic acid and dimethyl sulfoxide (Swern oxidation) or after other methods customary for the oxidation of hydroxymethyl compounds to aldehydes are oxidized to the aldehydes (XIII). In the fourth step [D], the aldehydes (XIII) are reacted with diethyl 2- (cyclohexylamino) vinyl phosphonate in inert solvents such as ethers, preferably in tetrahydrofuran in the presence of sodium hydride, in a temperature range from -20 C to +30 ° C, preferably from -5 ° C to room temperature in the compounds (IX).

The dihydropyridines of the general formula (X) used as starting materials are known or can be prepared by known methods [EP-A 88 276; DE-A 28 47 236].

The compounds of general formula (I) according to the invention are active ingredients for medicinal products. In particular, they are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HGM-CoA) reductase and consequently inhibitors of cholesterol biosynthesis. They can therefore be used to treat hyperlipoproteinemia, lipoproteinemia or arteriosclerosis. The active compounds according to the invention also bring about a reduction in the cholesterol content in the blood.

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. Here, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 98% by weight, preferably 1 to 90% by weight, of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.

• Wasser, nicht-toxische organische Lösungsmittel, wie Paraffine (z.B. Erdölfraktionen), pflanzliche Öle (z.B. Erdnuß/Sesamöl), Alkohole (z.b: Ethylalkohol, Glycerin), Trägerstoffe, wie z.B. natürliche Gesteinsmehle (z.B. Kaoline, Tonerden, Talkum, Kreide), synthetische Gesteinsmehle (z.B. hochdisperse Kieselsäure, Silikate), Zucker (z.B. Rohr-, Milch- und Traubenzucker), Emulgiermittel (z.B. Polyoxyethylen-FettsäureEster, Polyoxyethylen-Fettalkohol-Ether, Alkylsulfonate und Arylsulfonate), Dispergiermittel (z.B. Lignin-Sulfitablaugen, Methylcellulose, Stärke und Polyvinylpyrrolidon) und Gleitmittel (z.B. Magnesiumstearat, Talkum, Stearinsäure und Natriumlaurylsulfat).

Examples of auxiliary substances are:

• Water, non-toxic organic solvents, such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut / sesame oil), alcohols (e.g. ethyl alcohol, glycerin), carriers, such as natural rock flour (e.g. kaolins, clays, talc, chalk), synthetic rock flour (e.g. highly disperse silica, silicates), sugar (e.g. cane, milk and dextrose), emulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and aryl sulfonates), dispersants (e.g. lignin sulfite liquor, methyl cellulose and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application is carried out in the usual way, preferably orally, parenterally, perlingually or intravenously. In the case of oral use, tablets can of course also contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additives, such as starch, preferably potato starch, gelatin and the like, in addition to the carrier substances mentioned. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions, in addition to the auxiliaries mentioned above, the active ingredients can be mixed with various flavor enhancers or colorants.

In the case of parenteral use, solutions of the active ingredients can be used using suitable liquid carrier materials.

In general, it has proven to be advantageous to administer amounts of approximately 0.001 to 1 mg / kg, preferably approximately 0.01 to 0.5 mg / kg of body weight in the case of intravenous administration in order to achieve effective results, and the dosage is approximately in the case of oral administration 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the drug, the type of its formulation and the time or interval at which the administration takes place . In some cases it may be sufficient to make do with less than the minimum quantity mentioned above, while in other cases the above-mentioned upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

Manufacturing examples example 1 (E / Z) -4-carboxyethyl-5- (4-fluorophenyl) -2-methyl-pent-4-en-3-one

• Kp 0.5 mm : 127°C
• Ausbeute: 108,7 g (82,3% der Theorie)

62 g (0.5 mol) of 4-fluorobenzaldehyde and 79 g (0.5 mol) of ethyl isobutanoylacetate are placed in 300 ml of dry isopropanol and mixed with a mixture of 2.81 ml (28 mmol) of piperidine and 1.66 ml (29 mmol ) Acetic acid in 40 ml of isopropanol. The mixture is stirred at room temperature for 48 h, concentrated in vacuo and the residue is distilled in a high vacuum.

• Kp 0.5 mm: 127 ° C
• Yield: 108.7 g (82.3% of theory)

Example 2 Diethyl 1,4-dihydro-2,6-diisopropyl-4- (4-fluorophenyl) pyridine-3,5-dicarboxylic acid

• Ausbeute: 35 g (23,4% der Theorie)
• ¹H-NMR (CDCI₃): δ = 1,1 - 1,3 (m, 18H); 4,05 - 4,25 (m, 6H); 5,0 (s, 1H); 6,13 (s, 1H); 6,88 (m, 2H); 7,2 (m, 2H).

98 g (0.371 mol) of the compound from Example 1 are boiled under reflux with 58.3 g (0.371 mol) of ethyl 3-amino-4-methyl-pent-2-ene in 300 ml of ethanol for 18 hours. The mixture is cooled to room temperature, the solvent is evaporated off in vacuo and the unreacted starting materials are distilled off at 130 ° C. in a high vacuum. The remaining syrup is stirred with n-hexane and the precipitate which has precipitated is filtered off, washed with n-hexane and dried in a desiccator.

• Yield: 35 g (23.4% of theory)
• ¹ H NMR (CDCI ₃ ): δ = 1.1-1.3 (m, 18H); 4.05 - 4.25 (m, 6H); 5.0 (s, 1H); 6.13 (s, 1H); 6.88 (m. 2H); 7.2 (m, 2H).

Example 3 Diethyl 2,6-diisopropyl-4- (4-fluorophenyl) pyridine-3,5-dicarboxylic acid

• Ausbeute: 5,8 g (87,9% der Theorie)
• ¹H-NMR (CDCl₃): δ = 0,98 (t, 6H); 1,41 (d, 12H); 3,1 (m, 2H); 4,11 (q, 4H); 7,04 (m, 2H); 7,25 (m, 2H).

3.8 g (16.4 mmol) of 2,3-dichloro-5,6-dicyanp-benzoquinone and are added to a solution of 6.6 g (16.4 mmol) of the compound from Example 2 in 200 ml of methylene chloride pa stir for 1 h at room temperature. It is then suctioned off through diatomaceous earth, the methylene chloride phase is extracted three times with 100 ml of water each time and dried over magnesium sulfate. After concentration in vacuo, the residue is chromatographed on a column (100 g silica gel 70-230 mesh, φ 3.5 cm, with ethyl acetate / petroleum ether (1: 9).

• Yield: 5.8 g (87.9% of theory)
• ¹ H NMR (CDCl ₃ ): δ = 0.98 (t, 6H); 1.41 (d, 12H); 3.1 (m. 2H); 4.11 (q, 4H); 7.04 (m, 2H); 7.25 (m. 2H).

Example 4 3,5-dihydroxymethyl-2,6-diisopropyl-4- (4-fluorophenyl) pyridine

• Ausbeute: 2,4 g (66,7% der Theorie)
• ¹H-NMR (CDCl₃): δ = 1,35 (d, 12H); 3,43 (m, 2H); 4,47 (d, 4H); 7,05 - 7,3 (m, 4H).

Under nitrogen, 22.8 ml (80 mmol) of a 3.5 are added to a solution of 4.6 g (11.4 mmol) of the compound from Example 3 in 100 ml of dry tetrahydrofuran at -10 ° C. to -5 ° C. molar solution of sodium bis (2-methoxyethoxy) dihydroaluminate in toluene. The mixture is stirred at room temperature overnight and then heated to 40 ° C. for 5 h. After cooling again to 0 ° C., 100 ml of water are carefully added dropwise and the mixture is extracted three times with 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh, 3.5 cm, with ethyl acetate / petroleum ether (6: 4).

• Yield: 2.4 g (66.7% of theory)
• ¹ H NMR (CDCl ₃ ): δ = 1.35 (d, 12H); 3.43 (m, 2H); 4.47 (d. 4H); 7.05 - 7.3 (m, 4H).

Example-5 2,6-diisopropyl-4- (4-fluorophenyl) pyridine-3,5-dicarbaldehyde

• Ausbeute: 3,2 g (85,3% der Theorie)
• 'H-NMR (CDCl₃): δ = 1,33 (d, 12H); 3,85 (m, 2H); 7,1 -7,32 (m, 4H); 9,8 (s, 2H).

10.3 g (48 mmol) of pyridinium chlorochromate and 4.9 g (48 mmol) of neutral aluminum oxide are added to a solution of 3.8 g (12 mmol) of the compound from Example 4 in 100 ml of methylene chloride pa and the mixture is stirred at room temperature for 1 h . It is suctioned off through diatomaceous earth and washed with 300 ml of methylene chloride. The methylene chloride phase is concentrated in vacuo and the residue is chromatographed on a column (150 g of silica gel 70-230 mesh, φ 3.5 cm, with ethyl acetate / petroleum ether 2: 8).

• Yield: 3.2 g (85.3% of theory)
• 'H NMR (CDCl ₃ ): δ = 1.33 (d, 12H); 3.85 (m, 2H); 7.1 -7.32 (m, 4H); 9.8 (s, 2H).

Example 6 (E, E) -2,6-diisopropyl-4- (4-fluorophenyl) -3,5-di (prop-2-en-1-al-3-yl) pyridine

• Ausbeute: 920 mg (50% der Theorie)
• 'H-NMR (CDCl₃): δ = 1,33 (d, 12H); 3,33 (m, 2H); 6,03 (dd, 2H); 7,0 - 7,35 (m, 6H); 9,42 (d, 2H).

Under nitrogen, dropwise to a suspension of 0.36 g (12 mmol) of 80% sodium hydride in 20 ml of dry tetrahydrofuran at -5 C 3.1 g (12 mmol) of diethyl 2- (cyclohexylamino) vinyl phosphonate dissolved in 20 ml dry tetrahydrofuran. After 30 min. 1.6 g (5 mmol) of the compound from Example 5 in 20 ml of dry tetrahydrofuran are added dropwise at the same temperature and the mixture is heated under reflux for 30 min. After cooling to room temperature, the mixture is poured into 200 ml of ice-cold water and extracted three times with 100 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate. After concentration in vacuo, the residue is taken up in 50 ml of toluene, a solution of 2 g (15 mmol) of oxalic acid dihydrate in 25 ml of water is added and the mixture is heated under reflux for 30 min. After cooling to room temperature, the phases are separated, the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh, 0 3.5 cm, with ethyl acetate / petroleum ether 2: 8).

• Yield: 920 mg (50% of theory)
• 'H NMR (CDCl ₃ ): δ = 1.33 (d, 12H); 3.33 (m, 2H); 6.03 (dd, 2H); 7.0 - 7.35 (m, 6H); 9.42 (d. 2H).

Example 7 2,6-diisopropyl-4- (4-fluorophenyl) -3,5-di- (mothyl- (E) -5-hydroxy-3-oxo-hept-6-enoat-7-yl) pyridine

• Ausbeute: 800 mg (53,6% der Theorie)
• ¹H-NMR (CDCl₃): δ = 1,25 (m, 12H); 2,47 (m, 4H); 3,25 (m, 2H); 3,42 (s, 4H); 3,73 (s, 6H); 4,5 (m, 2H); 5,25 (dd, 2H); 6,35 (dd, 2H); 7,0 (m, 4H).

Under nitrogen, dropwise to a suspension of 360 mg (12 mmol) of 80% sodium hydride in 30 ml of dry tetrahydrofuran at -5 ° C 1.16 g (10 mmol) of methyl acetoacetate in 5 ml of dry tetrahyrofuran. After 15 min at the same temperature 6.2 ml (10 mmol) of 15% butyllithium in n-hexane are added dropwise and 15 min. stirred. Then 912 mg (2.5 mmol) of the compound from Example 6 dissolved in 20 ml of dry tetrahydrofuran are added dropwise and the mixture is stirred at -5 ° C. for 30 min. The reaction solution is carefully mixed with 3 ml of 50% acetic acid, diluted with 100 ml of water and the mixture extracted three times with 100 ml of ether. The combined organic phases are washed twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (80 g of silica gel 70-230 mesh, φ 3 cm, with ethyl acetate / petroleum ether 1: 1).

• Yield: 800 mg (53.6% of theory)
• ¹ H NMR (CDCl ₃ ): δ = 1.25 (m, 12H); 2.47 (m, 4H); 3.25 (m. 2H); 3.42 (s, 4H); 3.73 (s, 6H); 4.5 (m. 2H); 5.25 (dd, 2H); 6.35 (dd, 2H); 7.0 (m, 4H).

Example 8 2,6-diisopropyl-4- (4-fluorophenyl) -3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) pyridine

• Ausbeute: 400 mg (51,4% der Theorie)
• ¹H-NMR (CDCI₃): δ = 12,5 (m, 12H); 1,4 (m, 4H); 2,42 (m, 4H); 3,3 (m, 2H); 3,72 (s, 6H); 4,1 (m, 2H); 4,3 (m, 2H); 5,25 (dd, 2H); 6,3 (dd, 2H); 7,0 (m, 4H).

3.2 ml (3.2 mmol) of a 1 M triethylborane solution in tetrahydrofuran are added to a solution of 776 mg (1.3 mmol) of the compound from Example 7 in 30 ml of dry tetrahydrofuran at room temperature, and air is passed through for 5 minutes the solution and cools to -30 C internal temperature. 122 mg (3.2 mmol) of sodium borohydride and slowly 2.5 ml of methanol are added, the mixture is stirred at -30 ° C. for 30 minutes and a mixture of 10 ml of 30% hydrogen peroxide and 20 ml of water is then added. The temperature is allowed to rise to 0 C and stirring is continued for 30 min. The mixture is extracted three times with 50 ml of ethyl acetate, the combined organic phases are washed once with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (50 g of silica gel 230-400 mesh, φ 2.5 cm, with ethyl acetate / petroleum ether 1: 1).

• Yield: 400 mg (51.4% of theory)
• ¹ H NMR (CDCI ₃ ): δ = 12.5 (m, 12H); 1.4 (m, 4H); 2.42 (m, 4H); 3.3 (m. 2H); 3.72 (s, 6H); 4.1 (m. 2H); 4.3 (m. 2H); 5.25 (dd, 2H); 6.3 (dd, 2H); 7.0 (m, 4H).

Example 9 (E Z) -4-carboxyethyl-2-methyl-5-phenyl-pent-4-en-3-one

• Kp 0.5 mm : 130 °C
• Ausbeute: 60.7 g (56,2% der Theorie)

6.9 g (0.44 mol) of ethyl isobutanoylacetate and 46.3 g (0.44 mol) of benzaldehyde are placed in 300 ml of isopropanol, with a mixture of 2.5 ml (25 mmol) of piperidine and 1.5 ml (26 mmol) Acetic acid in 40 ml of isopropanol was added and the mixture was stirred at room temperature for 24 h. The mixture is concentrated in vacuo and the residue is distilled under high vacuum.

• Kp 0.5 mm: 130 ° C
• Yield: 60.7 g (56.2% of theory)

Example 10 Diethyl 1,4-dihydro-2,6-diisopropyl-4-phenyl-pyridine-3,5-dicarboxylate

• Ausbeute: 7,2 g (15,1% der Theorie)
• 'H-NMR (CDCl₃): δ = 1,2 (m, 18 H); 4,1 (m, 4H); 4,21 (m, 2H); 5,02 (s, 1H); 6,13 (s, 1H); 7,2 (m, 5H).

29.5 g (120 mmol) of the compound from Example 9 and 18.8 g (120 mmol) of 3-amino-4-methyl-pent-2-enoate are boiled under reflux in 150 ml of ethanol for 48 hours. The mixture is cooled, concentrated in vacuo and the residue is chromatographed on a column (500 g silica gel, 70-230 mesh, φ 5 cm, with ethyl acetate / pstrol ether 1: 9).

• Yield: 7.2 g (15.1% of theory)
• 'H NMR (CDCl ₃ ): δ = 1.2 (m, 18 H); 4.1 (m, 4H); 4.21 (m. 2H); 5.02 (s, 1H); 6.13 (s, 1H); 7.2 (m, 5H).

Example 11 Diethyl 2,6-diisopropyl-4-phenyl-pyridine-3,5-dicarboxylate

7.2 g (18.2 mmol) of the compound from Example 10 are reacted analogously to Example 3. Yield: 6.4 g (88.8% of theory)

Example 12 3,5-dihydroxymethyl-2,6-diisopropyl-4-phenyl-pyridine

• Ausbeute: 4 g (83,3% der Theorie)
• ¹H-NMR (CDCl₃): 5 = 1,3 (d, 12H); 3,5 (m, 2H); 4,3 (d, 4H); 7,35 (m, 5H).

40.5 ml (40.5 mmol) of a 1 molar solution of lithium aluminum hydride in ether are added dropwise under nitrogen to a solution of 6.4 g (16.2 mmol) of the compound from Example 11 in 100 ml of dry tetrahydrofuran at 0 ° C. . The mixture is stirred overnight at room temperature, heated to 50 ° C. for 3 h and cooled again to 0 ° C. 200 ml of water are carefully added dropwise to the mixture, suction filtered over diatomaceous earth and washed with 250 ml of ether. The organic phase is separated off, washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is stirred with petroleum ether, the precipitate is filtered off and dried in a desiccator.

• Yield: 4 g (83.3% of theory)
• ¹ H NMR (CDCl ₃ ): 5 = 1.3 (d, 12H); 3.5 (m, 2H); 4.3 (d. 4H); 7.35 (m, 5H).

Example 13 2,6-diisopropyl-4-phenyl-pyridine-3,5-dicarbaldehyde

• 'H-NMR (CDCl₃): δ = 1,35 (d, 12H); 3,4 (m, 2H); 7,3 (m, 2H); 7,5 (m, 3H); 9,3 (s, 2H).

4 g (13.3 mmol) of the compound from Example 12 are reacted analogously to Example 5. Yield: 3.4 g (87.2% of theory)

• 'H NMR (CDCl ₃ ): δ = 1.35 (d, 12H); 3.4 (m. 2H); 7.3 (m. 2H); 7.5 (m. 3H); 9.3 (s, 2H).

Example 14 (E, E) -2,6-Dilsopropyl-4-phenyl-3,5-di- (prop-2-en-1-al-3-yl) pyridine n

• 'H-NMR (CDCl₃): δ = 1,35 (d, 12H); 3,47 (m, 2H); 6,04 (dd, 2H); 7,0 - 7,45 (m, 7H); 9,4 (d, 2H).

3.35 g (11.4 mmol) of the compound from Example 13 are reacted analogously to Example 6. Yield: 2.7 g (67.5% of theory)

• 'H NMR (CDCl ₃ ): δ = 1.35 (d, 12H); 3.47 (m, 2H); 6.04 (dd, 2H); 7.0 - 7.45 (m, 7H); 9.4 (d. 2H).

Example 15 2,6-diisopropyl-4-phenyl-3,5-di- (methyl- (E) -5-hydroxy-3-oxo-hept-6-enoat-7-yl) pyridine

• ¹H-NMR (CDCI₃): δ = 1,25 (m, 12H); 2,35 (m, 4H); 3,27 (m, 2H); 3,40 (s, 4H); 3,75 (s, 6H); 4,38 (m, 2H); 5,25 (dd, 2H); 6,37 (dd, 2H); 7,02 (m, 2H); 7,30 (m, 3H).

2.7 g (7.8 mmol) of the compound from Example 14 are reacted analogously to Example 7. Yield: 3.2 g (71.1% of theory)

• ¹ H NMR (CDCI ₃ ): δ = 1.25 (m, 12H); 2.35 (m, 4H); 3.27 (m. 2H); 3.40 (s, 4H); 3.75 (s, 6H); 4.38 (m. 2H); 5.25 (dd, 2H); 6.37 (dd, 2H); 7.02 (m, 2H); 7.30 (m, 3H).

Example 16 2,6-diisopropyl-4-phenyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) pyridine

• ¹H-NMR (CDCl₃): δ = 1,25 (m, 12H); 1,3 - 1,7 (m, 4H); 2,39 (m, 4H); 3,2 - 3,4 (m, 2H); 3,71 (s, 6H); 4,02 (m, 2H); 4,27 (m, 2H); 5,3 (m, 2H); 6,32 (m, 2H); 7,0 (m, 2h); 7,25 (m, 3H).

3.2 g (5.5 mmol) of the compound from Example 15 are reacted analogously to Example 8. Yield: 2 g (62.5% of theory)

• ¹ H NMR (CDCl ₃ ): δ = 1.25 (m, 12H); 1.3 - 1.7 (m, 4H); 2.39 (m, 4H); 3.2 - 3.4 (m, 2H); 3.71 (s, 6H); 4.02 (m, 2H); 4.27 (m. 2H); 5.3 (m, 2H); 6.32 (m. 2H); 7.0 (m, 2h); 7.25 (m. 3H).

Example 17 (E / Z) -2-ethoxycarbonyl-1- (4-fluorophenyl) but-2-en-3-one

• Kp 0,5 mm: 138°C
• Ausbeute: 50,5 g (45,5% der Theorie)

62 g (0.5 mol) of 4-fluorobenzaldehyde and 53.9 ml (0.5 mol) of methyl acetoacetate are placed in 300 ml of isopropanol, with a mixture of 2.81 ml (28 mmol) of piperidine and 1.66 ml (29 mmol) of acetic acid in 40 ml of isopropanol and stirred for 48 h at room temperature. The mixture is concentrated in vacuo and the residue is distilled under high vacuum.

• Kp 0.5 mm: 138 ° C
• Yield: 50.5 g (45.5% of theory)

Example 18 1,4-Dihydro-2,6-dimethyl-4- (4-fluorophenyl) pyridine-3,5-dicarboxylic acid dimethyl ester

• 'H-NMR (CDCl₃): δ = 2,33 (s, 6H); 3,65 (s, 6H); 4,99 (s, 1H); 5,77 (s, 1H); 6,89 (m, 2H); 7,22 (m, 2H).

33.3 g (0.15 mol) of the compound from Example 17 are refluxed with 17.3 g (0.15 mol) of 3-aminocrotonic acid methyl ester in 150 ml of ethanol for 4 h. The mixture is cooled to 0 ° C., the precipitate which has separated out is filtered off with suction, washed with a little petroleum ether and dried in a desiccator. Yield: 32 g (66.8% of theory)

• 'H NMR (CDCl ₃ ): δ = 2.33 (s, 6H); 3.65 (s, 6H); 4.99 (s, 1H); 5.77 (s, 1H); 6.89 (m. 2H); 7.22 (m, 2H).

Example 19 2,6-Dimethyl-4- (4-fluorophenyl) pyridine-3,5-dicarboxylic acid dimethyl ester

• 'H-NMR (CDCI₃): δ = 2,59 (s, 6H); 3,56 (s, 6H); 7,08 (m, 2H); 7,25 (m, 2H).

32 g (0.1 mol) of the compound from Example 18 are reacted analogously to Example 3. Yield: 27.2 g (87% of theory)

• 'H NMR (CDCI ₃ ): δ = 2.59 (s, 6H); 3.56 (s, 6H); 7.08 (m, 2H); 7.25 (m. 2H).

Example 20 3,5-dihydroxymethyl-2,6-dimethyl-4- (4-fluorophenyl) pyridine

• Ausbeute: 3,5 g (53,8% der Theorie)
• ¹H-NMR (CDCl₃): 5 = 2,81 (s, 6H); 4,28 (d, 4H); 7,1 (m, 2H); 7,3 (m, 2H).

Under nitrogen, 25 ml (87.5 mmol) of a 3.5 molar solution of sodium bis () are added to a solution of 7.9 g (25 mmol) of the compound from Example 19 in 100 ml of dry tetrahydrofuran at 0 ° C. 2-methoxyethoxy) dihydroaluminate in toluene. The mixture is stirred at room temperature for 6 h, cooled again to 0 ° C. and 200 ml of water are slowly added dropwise. The mixture is extracted three times with 150 ml of ethyl acetate, the combined organic phases are washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is stirred with ether, suction filtered and dried in a desiccator.

• Yield: 3.5 g (53.8% of theory)
• ¹ H NMR (CDCl ₃ ): 5 = 2.81 (s, 6H); 4.28 (d. 4H); 7.1 (m. 2H); 7.3 (m, 2H).

Example 21 2,6-dimethyl-4- (4-fluorophenyl) pyridine-3,5-carbaldehyde

• ¹H-NMR (CDCI₃): δ = 2,88 (s, 6H); 7,28 (m, 4H); 9,82 (s, 2H).

3.5 g (13.4 mmol) of the compound from Example 20 are reacted analogously to Example 5. Yield: 1.7 g (53% of theory)

• ¹ H NMR (CDCI ₃ ): δ = 2.88 (s, 6H); 7.28 (m. 4H); 9.82 (s, 2H).

Example 22 (E, E) -2,6-dimethyl-4- (4-fluorophenyl) -3,5-bis (prop-en-1-al-3-yl) pyridine

• ¹H-NMR (CDCl₃): δ = 2,7 (s, 6H); 6,15 (dd, 2H); 7,15 (m, 6H); 9,43 (d, 2H).

1.7 g (7 mmol) of the compound from Example 21 are reacted analogously to Example 6. Yield: 1 g (47.6% of theory)

• ¹ H NMR (CDCl ₃ ): δ = 2.7 (s, 6H); 6.15 (dd, 2H); 7.15 (m. 6H); 9.43 (d. 2H).

Example 23 2,6-Dsmethyl-4- (4-fluorophenyl) -3,5-di- (methyl- (E) -5-hydroxy-3-oxo-hept-6-enoat-7-yl) pyridine

• 'H-NMR (CDCl₃): 0 = 2,50 (m, 4H); 2,55 (s, 6H); 3,45 (s, 4H); 3,73 (s, 6H); 4,52 (m, 2H); 5,35 (dd, 2H); 6,28 (d. 2H); 7,05 (m, 4H) ppm.

1 g (3.2 mmol) of the compound from Example 22 are reacted analogously to Example 7. Yield: 1 g (57% of theory)

• 'H NMR (CDCl ₃ ): 0 = 2.50 (m, 4H); 2.55 (s, 6H); 3.45 (s, 4H); 3.73 (s, 6H); 4.52 (m. 2H); 5.35 (dd, 2H); 6.28 (d. 2H); 7.05 (m, 4H) ppm.

Example 24 2,6-Dimethyl-4- (4-fluorophenyl) -3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) pyridine

• 'H-NMR (CDCl₃): δ = 1,20-1,60 (m, 4H); 2,43 (m, 4H); 2,54 (s, 6H); 3,72 (s, 6H); 4,09 (m, 2H); 4,33 (m, 2H); 5,37 (dd, 2H); 6,22 (d, 2H); 7,03 (m, 4H) ppm.

1 g (1.8 mmol) of the compound from Example 23 are reacted analogously to Example 8. Yield: 0.7 g (69.9% of theory)

• 'H NMR (CDCl ₃ ): δ = 1.20-1.60 (m, 4H); 2.43 (m, 4H); 2.54 (s, 6H); 3.72 (s, 6H); 4.09 (m. 2H); 4.33 (m, 2H); 5.37 (dd, 2H); 6.22 (d. 2H); 7.03 (m, 4H) ppm.

Example 25 1,4-Dihydro-4- (4-fluorophenyl) -2-isopropyl-6-methyl-pyridine-3,5-dicarboxylic acid 3-ethyl-5-methyl ester

• Ausbeute: 13,6 g (66,3% der Theorie)
• ¹H-NMR (CDCl₃): δ = 1,2 (m, 9H); 2,35 (s, 3H); 3,65 (s, 3H); 4,12 (m, 3H); 4,98 (s, 1H); 5,75 (s, 1H); 6,88 (m, 2H); 7,25 (m, 2H).

15 g (56.8 mol) of the compound from Example 1 and 6.5 g (56.8 mmol) of 3-aminocrotonic acid methyl ester are refluxed in 150 ml of ethanol for 20 h. The mixture is cooled, filtered off and concentrated in vacuo. The residue is chromatographed on a column (250 g of silica gel 70-230 mesh, φ 4.5 cm, with ethyl acetate / petroleum ether 3: 7).

• Yield: 13.6 g (66.3% of theory)
• ¹ H NMR (CDCl ₃ ): δ = 1.2 (m, 9H); 2.35 (s, 3H); 3.65 (s, 3H); 4.12 (m, 3H); 4.98 (s, 1H); 5.75 (s, 1H); 6.88 (m. 2H); 7.25 (m. 2H).

Example 26 4- (4-fluorophenyl) -2-isopropyl-6-methyl-pyridine-3,5-dicarboxylic acid 3-ethyl-5-methyl ester

• ¹H-NMR (CDCI₃): δ = 0,98 (t, 3H); 1,31 (d, 6H); 2,6 (s, 3H); 3,11 (m, 1H); 3,56 (s, 3H); 4,03 (q, 2H); 7,07 (m, 2H); 7,25 (m, 2H).

13.5 g (37.4 mmol) of the compound from Example 25 are reacted analogously to Example 3. Yield: 9.5 g (70.9% of theory)

• ¹ H NMR (CDCI ₃ ): δ = 0.98 (t, 3H); 1.31 (d, 6H); 2.6 (s. 3H); 3.11 (m, 1H); 3.56 (s. 3H); 4.03 (q, 2H); 7.07 (m, 2H); 7.25 (m. 2H).

Example 27 3,5-dihydroxymethyl-4- (4-fluorophenyl) -2 _- isopropyl-6-methyl-pyridine

• Ausbeute: 11,5 g (68,9% der Theorie)
• 'H-NMR (CDC1₃): δ = 1,3 (d, 6H); (s, 3H); 3,51 (m, 1H); 4,3 (m, 4H); 7,1 (m, 2H); 7,3 (m, 2H).

20.7 g (57.7 mmol) of the compound from Example 26 dissolved in 50 ml of absolute tetrahydrofuran are slowly added dropwise under nitrogen to a suspension of 6 g (158 mmol) of lithium aluminum hydride in 200 ml of absolute tetrahydrofuran at 60 ° C. The mixture is heated to reflux for 1 h, cooled to 0 ° C. and carefully mixed with 18 ml of water. 6 ml of 10% potassium hydroxide solution are added, the precipitate is filtered off with suction and the residue is boiled twice with 250 ml of ether each time. The combined mother liquors are dried over magnesium sulfate and concentrated in vacuo. The residue is stirred with petroleum ether, suction filtered and dried in a desiccator.

• Yield: 11.5 g (68.9% of theory)
• 'H NMR (CDC1 ₃ ): δ = 1.3 (d, 6H); (s, 3H); 3.51 (m, 1H); 4.3 (m. 4H); 7.1 (m. 2H); 7.3 (m, 2H).

Example 28 4- (4-fluorophenyl) -2-isopropyl-6-methyl-pyridine-3,5-dicarbaldehyde

• ¹H-NMR (CDCl₃): δ = 1,32 (d, 6H); 2,88 (s, 3H); 3,87 (m, 1H); 7,25 (m, 4H); 9,81 (d, 2H).

11.5 g (40 mmol) of the compound from Example 27 are reacted analogously to Example 5. Yield: 7.3 g (64% of theory)

• ¹ H NMR (CDCl ₃ ): δ = 1.32 (d, 6H); 2.88 (s, 3H); 3.87 (m, 1H); 7.25 (m. 4H); 9.81 (d. 2H).

Example 29 (E, E) -4- (4-fluorophenyl) -2-isopropyl-6-methyl-3,5-di- (prop-2-en-1-al-3-yl) pyridine

• ¹H-NMR (CDCl₃): δ = 1,32 (d, 6H); 2,7 (s, 3H); 3,34 (m, 1 H); 6,02 (dd, 1 H); 6,15 (dd, 1 H); 7,0 - 7,35 (m, 6H); 9,42 (d, 1 H); 9,43 (d, 1 H).

7.3 g (21.7 mmol) of the compound from Example 28 are reacted analogously to Example 6. Yield: 6.35 g (86.9% of theory)

• ¹ H NMR (CDCl ₃ ): δ = 1.32 (d, 6H); 2.7 (s. 3H); 3.34 (m, 1H); 6.02 (dd, 1H); 6.15 (dd, 1H); 7.0 - 7.35 (m, 6H); 9.42 (d, 1H); 9.43 (d, 1H).

Example 30 4- (4-fluorophenyl) -2-isopropyl-6-methyl-3,5-di- (methyl- (E) -5-hydroxy-3-oxo-hept-6-enoat-7-yl) pyridine

• ¹H-NMR (CDCI₃): δ = 1,25 (d, 6H); 2,42 (m, 2H); 2,53 (m, 2H); 2,57 (s, 3H); 3,28 (m, 1H); 3,42 (s, 2H); 3,43 (s, 2H); 3,75 (s, 6H); 4,52 (m, 2H); 5,25 (dd, 1 H); 5,36 (dd, 1 H); 6,28 (d, 1 H); 6,37 (d, 1 H); 6,90 - 7,20 (m, 4H).

6.3 g (18.8 mol) of the compound from Example 29 are reacted analogously to Example 7. Yield: 5.7 g (53.5% of theory)

• ¹ H NMR (CDCI ₃ ): δ = 1.25 (d, 6H); 2.42 (m, 2H); 2.53 (m. 2H); 2.57 (s, 3H); 3.28 (m, 1H); 3.42 (s, 2H); 3.43 (s, 2H); 3.75 (s, 6H); 4.52 (m. 2H); 5.25 (dd, 1H); 5.36 (dd, 1H); 6.28 (d, 1H); 6.37 (d, 1H); 6.90 - 7.20 (m, 4H).

Example 31 4- (4-fluorophenyl) -2-isopropyl-6-methyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) pyridine

• 'H-NMR (CDCl₃): δ = 1,25 (m, 6H); 1,2 - 1,5 (m, 4H); 2,41 (m, 4H); 2,57 (s, 3H); 3,3 (m, 1 H); 3,72 (s, 6H); 4,1 (m, 2H); 4,3 (m, 2H); 5,15 - 5,5 (m, 2H); 6,15 -6,45 (m, 2H); 7,0 (m, 4H).

5.7 g (10 mmol) of the compound from Example 30 are reacted analogously to Example 8. Yield: 2.9 g (50.8% of theory)

• 'H NMR (CDCl ₃ ): δ = 1.25 (m, 6H); 1.2 - 1.5 (m, 4H); 2.41 (m, 4H); 2.57 (s, 3H); 3.3 (m, 1H); 3.72 (s, 6H); 4.1 (m. 2H); 4.3 (m. 2H); 5.15 - 5.5 (m, 2H); 6.15 -6.45 (m, 2H); 7.0 (m, 4H).

Example 32 Diethyl 1,4-dihydro-2-ethyl-4- (4-fluorophenyl) -6-isopropyl-pyridine-3,5-dicarboxylic acid

• Ausbeute: 5,3 g (19,3 % der Theorie)

9.5 g (73.6 mmol) of methyl 3-amino-pent-2-ene and 19.4 g (73.6 mmol) of the compound from Example 1 are boiled under reflux in 200 ml of n-butanol for 5 hours. The mixture is cooled to room temperature, the solvent is concentrated in vacuo and the residue is chromatographed on a column (silica gel 70-230 mesh, with petroleum ether / ethyl acetate 9: 1).

• Yield: 5.3 g (19.3% of theory)

Example 33 2-ethyl-4- (4-fluorophenyl) -6-isopropyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) pyridine

• ¹H-NMR (CDCl₃): δ = 1,28 (m, 9H); 1,43 (M, 4H); 2,42 (m, 4H); 2,82 (q, 2H); 3,32 (m, 1 H); 3,72 (s, 6H); 4,09 (m, 2H); 4,32 (m, 2H); 5,28 (m, 2H); 6,30 (m, 2H); 7,00 (m, 4H) ppm

Example 33 was prepared from the compound from Example 32 in analogy to the reactions from Examples 3, 27, 5, 6, 7, 8:

• ¹ H NMR (CDCl ₃ ): δ = 1.28 (m, 9H); 1.43 (M, 4H); 2.42 (m, 4H); 2.82 (q, 2H); 3.32 (m, 1H); 3.72 (s, 6H); 4.09 (m. 2H); 4.32 (m, 2H); 5.28 (m, 2H); 6.30 (m, 2H); 7.00 (m, 4H) ppm

Example 34 Diethyl 1,4-dihydro-4- (4-fluorophenyl) -2-isopropyl-6-n-propyl-pyridine-3,5-dicarboxylic acid

• Ausbeute: 2,6 g (17,7 % der Theorie).

5.8 g (36.8 mmol) of 3-amino-hex-2-enoic acid ethyl ester and 9.7 g (36.8 mmol) of the compound from Example 1 are boiled under reflux in 100 ml of ethanol pA for 48 hours. The mixture is cooled, the solvent is concentrated in vacuo and the residue is chromatographed on a column (silica gel 70-230 mesh, with petroleum ether / ethyl acetate 8: 2).

• Yield: 2.6 g (17.7% of theory).

Example 35 4- (4-fluorophenyl) -2-isopropyl-6-n-propyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) - pyridine

• 'H-NMR (CDCl₃): δ = 0,98 (t, 3H); 1,22 (d, 6H); 1,38 (m, 4H); 1,77 (m, 2H); 2,40 (m, 4H); 2,78 (m, 2H); 3,28 (m, 1 H); 3,70 (s, 6H); 4,05 (m, 2H); 4,28 (m, 2H); 5,25 (m, 2H); 6,28 (m, 2H); 6,95 (m, 4H) ppm.

Example 35 was prepared from the compound from Example 34 in analogy to the reactions from Examples 3, 27, 5, 6, 7, 8.

• 'H NMR (CDCl ₃ ): δ = 0.98 (t, 3H); 1.22 (d, 6H); 1.38 (m, 4H); 1.77 (m. 2H); 2.40 (m, 4H); 2.78 (m, 2H); 3.28 (m, 1H); 3.70 (s, 6H); 4.05 (m. 2H); 4.28 (m. 2H); 5.25 (m. 2H); 6.28 (m. 2H); 6.95 (m, 4H) ppm.

Example 36 Diethyl 1,4-dihydro-2-n-butyl-4- (4-fluorophenyl) -6-isopropyl-pyridine-3,5-dicarboxylic acid

• Ausbeute: 2,5 g (16,4 % der Theorie)

6.3 g (36.8 mmoi) of 3-amino-hept-2-enoic acid ethyl ester and 9.7 g (36.8 mmol) of the compound from Example 1 are reacted analogously to Example 34.

• Yield: 2.5 g (16.4% of theory)

Example 37 2-n-butyl-4- (4-fluorophenyl) -6-isopropyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) - pyridine

Example 37 was prepared from the compound from Example 36 in analogy to the reactions from Examples 3, 27, 5, 6, 7, 8.

Example 38 Diethyl 1,4-dihydro-2-benzyl-4- (4-fluorophenyl) -6-isopropyl-pyridine-3,5-dicarboxylic acid

• Ausbeute: 2,1 g (12,6 % der Theorie).

7.4 g (36.8 mmol) of 3-amino-4-phenyl-crotonic acid ethyl ester and 9.7 g (36.8 mmol) of the compound from Example 1 are reacted analogously to Example 34.

• Yield: 2.1 g (12.6% of theory).

Example 39 2-Benzyl-4- (4-fluorophenyl) -6-isopropyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) pyridine

• ¹H-NMR (CDCl₃): 5 = 1,10-1,50 (m, 10H); 2,40 (m, 4H); 3,32 (m, 1H); 3,72 (s, 3H); 3,73 (s, 3H); 3,98 (m, 1 H); 4,08 (m, 1 H); 4,18 (m, 1 H); 4,21 (s, 2H); 4,28 (m, 1 H); 5,13 (dd, 1 H); 5,27 (dd, 1 H); 6,25 (d, 1 H); 6,33 (d, 1 H); 6,97 (m, 4H), 7,25 (m, 5H) ppm.

Example 39 was prepared from the compound from Example 38 in analogy to the reactions from Examples 3, 27, 5, 6, 7, 8.

• ¹ H NMR (CDCl ₃ ): 5 = 1.10-1.50 (m, 10H); 2.40 (m, 4H); 3.32 (m, 1H); 3.72 (s, 3H); 3.73 (s, 3H); 3.98 (m, 1H); 4.08 (m, 1H); 4.18 (m, 1H); 4.21 (s, 2H); 4.28 (m, 1H); 5.13 (dd, 1H); 5.27 (dd, 1H); 6.25 (d, 1H); 6.33 (d, 1H); 6.97 (m, 4H), 7.25 (m, 5H) ppm.

Example 40 (E / Z) -2-carboxyethyl-1-cyclopropyl-3- (4-fluorophenyl) prop-2-en-1-one

• Kp 0,5 mm: 140°C
• Ausbeute: 52,3 g (79,8 % der Theorie)

39 g (0.25 mol) of ethyl cyclopropylcarbonyl acetate and 31 g (0.25 mol) of 4-fluorobenzaldehyde are placed in 150 ml of dry isopropanol and mixed with a mixture of 1.4 ml (14 mmol) of piperidine and 0.83 ml (14, 5 mmol) acetic acid in 20 ml isopropanol. The mixture is stirred for 48 hours at room temperature. concentrated in vacuo and distilled the residue in a high vacuum.

• Kp 0.5 mm: 140 ° C
• Yield: 52.3 g (79.8% of theory)

Example 41 Diethyl 1,4-dihydro-2-cyclopropyl-4- (4-fluoropheny!) - 6-isopropyl-pyridine-3,5-dicarboxylic acid

• 'H-NMR (CDCl₃): δ = 0,65 (m, 2H); 1,03 (m, 2H); 1,15 (m, 13H); 2,78 (m, 1H); 4,15 (m, 4H); 5,03 (s, 1H); 5,72 (s, 1 H); 6,90 (m, 2H); 7,22 (m, 2H) ppm.

39.3 g (0.15 mol) of the compound from Example 40 and 23.6 g (0.15 mol) of 3-amino-4-methyl-pent-2-enoic acid ethyl ester are dissolved in 150 ml of ethylene glycol overnight cooked under reflux. After cooling to room temperature, the mixture is extracted several times with ether, and the combined ether phases are washed three times with 10% hydrochloric acid, once each with water and saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue is stirred with petroleum ether / ether, suction filtered and dried in a desiccator. Yield: 22.8 g (37.9% of theory)

• 'H NMR (CDCl ₃ ): δ = 0.65 (m, 2H); 1.03 (m, 2H); 1.15 (m, 13H); 2.78 (m, 1H); 4.15 (m. 4H); 5.03 (s, 1H); 5.72 (s, 1H); 6.90 (m, 2H); 7.22 (m, 2H) ppm.

Example 42 2-Cyclopropyl-4- (4-fluorophenyl) -6-isopropyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) pyridine

• ¹H-NMR (CDCl₃): δ = 0,90 (m, 2H); 1,20 (d, 6H); 1,10-1,60 (m, 6H); 2,25 (m, 1H); 2,43 (m, 4H); 3,25 (m, 1 H); 3,73 (s, 6H); 4,08 (m, 2H); 4,30 (m, 2H); 5,22 (dd, 1 H); 5,53 (dd, 1 H); 6,30 (m, 2H); 6,98 (m, 4H) ppm.

Example 42 was prepared from the compound from Example 41 in analogy to the reactions from Examples 3, 27, 5, 6, 7, 8.

• ¹ H NMR (CDCl ₃ ): δ = 0.90 (m, 2H); 1.20 (d, 6H); 1.10-1.60 (m, 6H); 2.25 (m, 1H); 2.43 (m, 4H); 3.25 (m, 1H); 3.73 (s, 6H); 4.08 (m. 2H); 4.30 (m. 2H); 5.22 (dd, 1H); 5.53 (dd, 1H); 6.30 (m, 2H); 6.98 (m, 4H) ppm.

Example 43 3-Amino-3-cyclopropyl-acrylic acid ethyl ester

• Ausbeute: 11,9 g (24 % der Theorie).

49.9 g (0.32 mol) of ethyl cyclopropylcarbonyl acetate in 200 ml of dry toluene are mixed with 1.1 g of p-toluenesulfonic acid and saturated with ammonia gas at room temperature with stirring. After standing overnight, the mixture is boiled under reflux for 8 hours on a water separator, ammonia gas being introduced continuously. The mixture is allowed to cool overnight, filtered, the toluene solution is concentrated in vacuo and distilled from ⁰ to 65 C from the unreacted starting material in a high vacuum. The substance is then in the residue.

• Yield: 11.9 g (24% of theory).

Example 44 Diethyl 1,4-dihydro-2,6-dicyclopropyl-4- (4-fluorophenyl) pyridine-3,5-dicarboxylic acid

• Ausbeute: 10,4 g (65,1 % der Theorie)
• 'H-NMR (CDCl₃): δ = 0,60 (m, 4H); 0,95 (m, 4H); 1,23 (t, 6H); 2,72 (m, 2H); 4,12 (m, 4H); 5,02 (s, 1 H); 5,40 (s, 1 H); 6,88 (m, 2H); 7,20 (m, 2H) ppm.

6.2 g (40 mmol) of the compound from Example 43 and 10.5 g (40 mmol) of the compound from Example 40 are dissolved in 100 ml of ethylene glycol and refluxed overnight. After cooling down At room temperature, the mixture is extracted several times with ether, the organic phase is washed once each with 10% hydrochloric acid, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuo.

• Yield: 10.4 g (65.1% of theory)
• 'H NMR (CDCl ₃ ): δ = 0.60 (m, 4H); 0.95 (m, 4H); 1.23 (t, 6H); 2.72 (m, 2H); 4.12 (m, 4H); 5.02 (s, 1H); 5.40 (s, 1H); 6.88 (m. 2H); 7.20 (m, 2H) ppm.

Example 45 2,6-dicyclopropyl-4- (4-fluorophenyl) -3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) pyridine

• 'H-NMR (CDCl₃): δ = 0,85 (m, 4H); 1,08 (m, 4H); 1,20-1,60 (m, 4H); 2,20 (m, 2H); 2,43 (m, 4H); 3,70 (s, 6H); 4,12 (m, 2H); 4,33 (m, 2H); 5,52 (dd, 2H); 6,30 (d, 2H); 7,0 (m, 4H) ppm.

Example 45 was prepared from the compound from Example 44 in analogy to the reactions from Examples 3, 27, 5, 6, 7, 8.

• 'H NMR (CDCl ₃ ): δ = 0.85 (m, 4H); 1.08 (m, 4H); 1.20-1.60 (m, 4H); 2.20 (m, 2H); 2.43 (m, 4H); 3.70 (s, 6H); 4.12 (m, 2H); 4.33 (m, 2H); 5.52 (dd, 2H); 6.30 (d, 2H); 7.0 (m, 4H) ppm.

Example 46 (E, Z) -4-carboxyethyl-5- (4-fluoro-3-phenoxyphenyl) -2-methyl-pent-4-en-3-one

• Ausbeute: 110 g (wurde ohne weitere Reinigung in Beispiel 47 eingesetzt).

49 g (0.31 mol) of ethyl isobutanoylacetate and 67 g (0.31 mol) of 3-phenoxy-4-fluorobenzaldehyde are placed in 300 ml of isopropanol and mixed with a mixture of 1.81 ml (18 mmol) of piperidine and 1.067 ml (18 , 6 mmol) of acetic acid in 30 ml of isopropanol. The mixture is stirred overnight at room temperature, then concentrated in vacuo and dried in a high vacuum.

• Yield: 110 g (was used in Example 47 without further purification).

Example 47 Diethyl 1,4-dihydro-2,6-diisopropyl-4- (4-fluoro-3-phenoxyphenyl) pyridine-3,5-dicarboxylic acid

• ¹H-NMR (CDCl₃): δ = 1,05-1,25 (m, 18H); 4,05-4,2 (m, 6H); 4,95 (s, 1 H); 6,03 (s, 1 H); 6,85-7,1 (m, 6H); 7,3 (m, 2H).

30 g (84.3 mmol) of the compound from Example 46 and 13.2 g (84.3 mmol) of 3-amino-4-methyl-pent-2-enoic acid ethyl ester are refluxed in 150 ml of ethanol overnight cooked. The mixture is cooled to 0 ° C., the precipitate which has precipitated is filtered off, washed with petroleum ether and dried in a desiccator. Yield: 18.4 g (44.2% of theory)

• ¹ H NMR (CDCl ₃ ): δ = 1.05-1.25 (m, 18H); 4.05-4.2 (m, 6H); 4.95 (s, 1H); 6.03 (s, 1H); 6.85-7.1 (m, 6H); 7.3 (m, 2H).

Example 48 2,6-diisopropyl-4- (4-fluoro-3-phenoxyphenyl) -3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) - pyridine

Example 48 was prepared from the compound from Example 47 in analogy to the reactions from Examples 3, 27, 5, 6, 7, 8.

Example 49 (E / Z) -2-carboxyethyl-1- (4-tluorophenyl) -3-phenyl-propen-3-one

• 'H-NMR (CDCl₃): δ = 1,15 (t, 3H); 4,21 (q, 2H); 6,85-7,95 (m, 10H) ppm.

38.4 g (0.2 mol) of ethyl benzoylacetate and 24.8 g (0.2 mol) of 4-fluorobenzaldehyde are dissolved in 200 ml of toluene, mixed with 3 ml of piperidine and 3.5 ml of glacial acetic acid and heated under reflux overnight in a water separator. After cooling to room temperature, the mixture is extracted with saturated sodium bicarbonate solution and water, the organic phase is dried over magnesium sulfate and concentrated in vacuo. The unreacted starting materials are distilled off in a high vacuum and 55.9 g (93% of theory) of crude product are obtained in the distillation residue.

• 'H NMR (CDCl ₃ ): δ = 1.15 (t, 3H); 4.21 (q, 2H); 6.85-7.95 (m, 10H) ppm.

Example 50 Diethyl 1,4-dihydro-4- (4-fluorophenyl) -2-isopropyl-6-phenyl-pyridine-3,5-dicarboxylic acid

• Ausbeute: 8,6 g (19,7 % der Theorie)
• ¹H-NMR (CDCl₃): 5 = 0,85 (t, 3H); 1,20 (m, 9H); 3,85 (q, 2H); 4,12 (q, 2H); 4,25 (m, 1 H); 5,09 (m, 1 H); 5,93 (m, 1 H); 6,93 (m, 2H); 7,25-7,50 (m, 7H) ppm.

29.8 g (0.1 mol) of the compound from Example 49 and 15.7 g (0.1 mol) of 3-amino-4-methyl-pent-2-enoic acid ethyl ester are dissolved in 150 ml of ethylene glycol and refluxed overnight. After concentration in vacuo, the residue is dissolved in ethyl acetate, washed once with 10% hydrochloric acid, saturated sodium hydrogen carbonate solution and water, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (silica gel 70-230 mesh, with ethyl acetate / petroleum ether 1: 5).

• Yield: 8.6 g (19.7% of theory)
• ¹ H NMR (CDCl ₃ ): 5 = 0.85 (t, 3H); 1.20 (m, 9H); 3.85 (q, 2H); 4.12 (q, 2H); 4.25 (m, 1H); 5.09 (m, 1H); 5.93 (m, 1H); 6.93 (m, 2H); 7.25-7.50 (m, 7H) ppm.

Example 51 4- (4-fluorophenyl) -2-isopropyl-6-phenyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) pyridine

Example 51 was prepared from the compound from Example 50 in analogy to the reactions from Examples 3, 27, 5, 7, 8.

Example 52 (E / Z) -2- (carboxy-2-cyanoethyl) -3-cyclohexyl-1- (4-fluorophenyl) propen-3-one

• Ausbeute: 56,7 g (57,4 % der Theorie)

66.9 g (0.3 mol) of cyclohexylcarbonyl-acetic acid (2-cyanoethyl ester) and 37.2 g (0.3 mol) of 4-fluorobenzaldehyde were reacted analogously to Example 49.

• Yield: 56.7 g (57.4% of theory)

Example 53 1,4-Dihydro-2-cyclohexyl-4- (4-fluorophenyl) -6-isopropyl-pyridine-3,5-dicarboxylic acid-3-cyanoethyl ester-5-ethyl ester

• Ausbeute: 7,8 g (17,6 % der Theorie)

32.9 g (0.1 mol) of the compound from Example 52 and 15.7 g (0.1 mol) of 3-amino-4-methyl-pent-2-enoic acid ethyl ester are dissolved in 100 ml of ethanol and refluxed overnight. After concentration in vacuo, the residue is dissolved in ethyl acetate, washed once with 10% hydrochloric acid, saturated sodium bicarbonate solution and water, the organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (silica gel 70-230 mesh, with dichloromethane).

• Yield: 7.8 g (17.6% of theory)

Example 54 2-Cyclohexyl-4- (4-fluorophenyl) -6-isopropyl-pyridine-3,5-dicarboxylic acid-3-cyanoethyl ester-5-ethyl ester

• 'H-NMR (CDCl₃): δ = 0,98 (t, 3H); 1,33 (m, 10H); 1,82 (m, 6H); 2,35 (t, 2H); 2,69 (m, 1 H); 3,10 (m, 1H); 4,02 (q, 2H); 4,15 (t, 2H); 7,08 (m, 2H); 7,28 (m, 2H) ppm.

3.53 g (7.55 mmoi) of the compound from Example 53 are reacted analogously to Example 3. Yield: 2.96 g (84% of theory)

• 'H NMR (CDCl ₃ ): δ = 0.98 (t, 3H); 1.33 (m, 10H); 1.82 (m, 6H); 2.35 (t, 2H); 2.69 (m, 1H); 3.10 (m, 1H); 4.02 (q, 2H); 4.15 (t. 2H); 7.08 (m, 2H); 7.28 (m, 2H) ppm.

Example 55 2-cyclohexyl-3,5-dihydroxymethyl-4- (4-fluorophenyl) -6-isopropyl-pyridine

• Ausbeute: 1,64 g (86 % der Theorie)
• ¹H-NMR (CDCl₃): δ = 1,20-1,50 (m, 4H); 1,35 (d, 6H); 1,70-1,95 (m, 6H); 3,05 (m, 1 H); 3,43 (m, 1 H); 4,35 (s, 4H); 7,05-7,25 (m, 4H) ppm.

2.5 g (5.35 mmol) of the compound from Example 54 dissolved in 50 ml of dry toluene at -78 ° C. under a nitrogen atmosphere with 35.7 mol (53.5 mmol) of a 1.5 molar solution of diisobutylaluminum hydride in toluene mixed, stirred for 1 hour at -78 ° C and overnight at room temperature. The mixture is mixed with 20% potassium hydroxide solution under ice cooling and extracted several times with toluene. The organic phase is washed with water, dried over magnesium sulfate and concentrated in vacuo.

• Yield: 1.64 g (86% of theory)
• ¹ H NMR (CDCl ₃ ): δ = 1.20-1.50 (m, 4H); 1.35 (d. 6H); 1.70-1.95 (m, 6H); 3.05 (m, 1H); 3.43 (m, 1H); 4.35 (s, 4H); 7.05-7.25 (m, 4H) ppm.

Example 56 2-Cyclohexyl-4- (4-fluorophenyl) -6-isopropyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoat-7-yl) pyridine

• ¹H-NMR (CDCI₃): δ = 1,20-1,85 (m, 20H); 2,41 (m, 4H); 2,90 (m, 1H); 3,28 (m, 1H); 3,70 (s, 6H); 4,08 (m, 2H); 4,30 (m, 2H); 5,25 (dd, 2H); 6,30 (dd, 2H); 7,0 (m, 4H) ppm.

Example 56 was prepared from the compound from Example 55 in analogy to the reactions from Examples 5, 6, 7, 8.

• ¹ H NMR (CDCI ₃ ): δ = 1.20-1.85 (m, 20H); 2.41 (m, 4H); 2.90 (m, 1H); 3.28 (m, 1H); 3.70 (s, 6H); 4.08 (m. 2H); 4.30 (m. 2H); 5.25 (dd, 2H); 6.30 (dd, 2H); 7.0 (m, 4H) ppm.

Example 57 (E (2) -3-ethoxycarbonyl-1- (furan-2-yl) -4-methyl-penten-3-one

• Kp 0,5 mbar; 130°C

The compound was prepared analogously to Example 1 from furan-2-carbaldehyde. Yield: 93% of theory

• Kp 0.5 mbar; 130 ° C

Example 58 4- (furan-2-yl) -3,5-bis- [3,5-dihydroxy-6-methoxycarbonyl-hex-1-enyl] -2,6-diisopropyl-pyridine

• Farblose Kristalle, Schmelzpunkt 106°C
• 'H-NMR (CDCI₃): δ = 1,25 (m, 12H); 1,4 - 1,65 (m, 4H); 2,45 (m, 4H); 2,77 (d, 2H); 3,3 (m, 2H); 3,6 (m, 2H); 3,6 (d. 2H); 3,72 (s, 6H); 4,1 (m, 2H); 4,4 (m, 2H); 5,4 (dd, 2H); 6,12 (m, 1 H); 6,4 (m, 1 H); 6,5 (d, 2H); 7,45 (m. 1 H)

Example 58 was prepared from the compound from Example 57 analogously to the reactions of Examples 2, 3, 5, 6, 7, 8 and 55.

• Colorless crystals, melting point 106 ° C
• 'H NMR (CDCI ₃ ): δ = 1.25 (m, 12H); 1.4 - 1.65 (m, 4H); 2.45 (m, 4H); 2.77 (d. 2H); 3.3 (m. 2H); 3.6 (m. 2H); 3.6 (i.e. 2H); 3.72 (s, 6H); 4.1 (m. 2H); 4.4 (m. 2H); 5.4 (dd, 2H); 6.12 (m, 1H); 6.4 (m, 1H); 6.5 (d. 2H); 7.45 (m. 1 h)

Example 59 (E (2) -3-ethoxycarbonyl-4-methyl-1 (thiopen-2-yl) penten-3-one

• Ausbeute: 86 % der Theorie
• Kp 1,5 mbar: 145°C

Example 59 was prepared analogously to Example 1 from thiopene-2-carbaldehyde.

• Yield: 86% of theory
• Kp 1.5 mbar: 145 ° C

Example 60 3,5-bis- [3,5-dihydroxy-6-methoxycarbonyl-hex-1-enyl] -2,6-diisopropyl-4- (thiopen-2-yl) pyridine

• Farblose Kristalle, Schmelzpunkt 62" C
• ¹H-NMR (CDCI₃): 5 = 1,25 (m, 12H); 1,35 - 1,6 (m, 4H); 2,45 (m, 4H); 2,6 (s, 2H); 3,3 (m, 2H); 3,5 (d, 2H); 3,72 (s, 6H); 4,1 (m, 2H); 4,35 (m, 2H); 5,48 (dd, 2H); 6,4 (d, 2H); 6,74 (m, 1 H); 6,98 (m, 1 H); 7,28 (m, 1 H)

Example 60 was prepared from the compound from Example 59 analogously to Examples 2, 3, 5, 6, 7, 8 and 27.

• Colorless crystals, melting point 62 "C
• ¹ H NMR (CDCI ₃ ): 5 = 1.25 (m, 12H); 1.35 - 1.6 (m, 4H); 2.45 (m, 4H); 2.6 (s, 2H); 3.3 (m. 2H); 3.5 (d. 2H); 3.72 (s, 6H); 4.1 (m. 2H); 4.35 (m. 2H); 5.48 (dd, 2H); 6.4 (d. 2H); 6.74 (m, 1H); 6.98 (m, 1H); 7.28 (m, 1h)

Example 61 Disodium 2,6-diisopropyl-4-phenyl-3,5-di- (erythro- (E) -3,5-dihydroxyhept-6-enoat-7-yl) pyridine

• Ausbeute: 605 mg (96,5 % der Theorie).

583 mg (1 mmol) of the compound from Example 16 are dissolved in 10 ml of tetrahydrofuran. After adding 20 ml of 0.1 N NaOH, the mixture is left to stand at room temperature for 1 hour, concentrated in vacuo and then lyophilized the aqueous solution.

• Yield: 605 mg (96.5% of theory).

Application example Example 62

The enzyme activity determination was modified according to GC Ness et al., Archives of Biochemistry and Biophysics 197, 493-499 (1979). Male Ricorats (body weight 300-400 g) were treated for 11 days with altromin powder feed, to which 40 g cholestyramine / kg feed was added. After decapitation, the livers were removed from the animals and placed on ice. The livers were crushed and in the Potter-Elvejem homogenizer 3 times in 3 volumes of 0.1 m sucrose, 0.05 m KCI, 0.04 m K _x Hy phosphate, 0.03 m ethylenediaminetetraacetic acid, 0.002 m dithiothreitol (SPE) Buffer pH 7.2, homogenized. The mixture was then centrifuged at 15,000 * g for 15 minutes and the sediment was discarded. The supernatant was sedimented at 100,000 g for 75 minutes. The pellet is taken up in 1/4 volume of SPE buffer, homogenized again and then centrifuged again at 100,000 g for 60 minutes. The pellet is taken up with 5 times its volume of SPE buffer, homogenized and frozen and stored at -78 ° C (= enzyme solution).

For testing, the test compounds (or mevinolin as reference substance) were in dimethylformamide dissolved with the addition of 5 vol.% 1N NaOH and used with 10 μl in different concentrations in the enzyme test. The test was started after 20 minutes of pre-incubation of the compounds with the enzyme at 37 ° C. The test batch was 0.380 ml and contained 4 μmol glucose-6-phosphate, 1.1 mg bovine serum albumin, 2.1 μmol dithiothreitol, 0.35 μmol NADP, 1 unit glucose-6-phosphate dehydrogenase, 35 μmol K _x hy-phosphate pH 7 , 2, 20 ul enzyme preparation and 56 nmol of 3-hydroxy-3-methyl-glutaryl coenzyme A (glutaryl-3- ¹⁴ C) 100 000 dpm.

The mixture was incubated at 37 ° C. for 60 minutes and the reaction was stopped by adding 300 μl of 0.24 m HCl. After a post-incubation of 60 minutes at 37 ⁰ C, the mixture was centrifuged and 600 .mu.l of the supernatant on a 0.7 x 4 cm with Biorex @ 5-chloride 100-200 mesh (anion exchange) column filled applied. It was distilled with 2 ml. Wash the water and add 3 ml Aquasol to the flow plus wash water and count in the LKB scintillation counter. IC 50 values were determined by plotting the percentage inhibition against the concentration of the compound in the test by intrapolation. To determine the relative inhibitory potency, the IC 50 value of the reference substance mevinolin was set to 100 and compared with the simultaneously determined IC 50 value of the test compound.

Example 63

The subchronic effect of disubstituted pyridines on blood cholesterol levels in dogs was tested in feeding experiments lasting several weeks. For this purpose, the substance to be investigated was administered once daily in a capsule to healthy beagle dogs together with the food p.o. given. The feed was also present during the entire trial period, i.e. Before, during and after the application period of the substance to be investigated, colestyramine (4 g / 100 g feed) was added as a bile acid sequestrant. Venous blood was drawn from the dogs twice a week and the serum cholesterol was determined enzymatically. The serum cholesterol values during the application period were compared with the serum cholesterol values before the application period (controls).

For example, for the Na salt of example 8 (2,6-diisopropyl-4- (4-fluorophenyl) -3,5-di- (sodium erythro- (E) -3,5-dihydroxy-hept-6-enoate- 7-yl) -pyridine) after 2 weeks of application of 8 mg / kg po a 22.4% decrease in serum cholesterol.

Claims (14)

1. Disubstituted pyridines of the formula

in softer R '- Heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ may be substituted, wherein R ^d . R ^{S - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halo, cyano, nitro, trifluoromethyl, Trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkyisulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ , wherein R ⁴ and R ^{5 have} the meaning given above, R ² denotes cycloalkyl, or - Alkyl means that can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoro methyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁴ _R ⁵ , wherein R ⁴ , R ^{S - are the} same or different and alkyl; Mean aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, the heteroaryl and aryl radicals of the latter substituents being up to 3 times the same, different by tri-fluoro, identical or different by Trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl can be substituted, R ^{3 represents} hydrogen, or - Cycloalkyl means or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁴ R ⁵ , in which R ⁴ , R ^{5 have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, wherein the heteroaryl and aryl groups of up to 3 times by identical or different halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl , Alkoxy, alkylthio or alkylsulfonyl may be substituted, or - Heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ can be substituted, wherein R ⁴ and R ^{5 have} the meaning given above, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ , wherein R4. and R ^{5 have} the meaning given above, X is a group of the formula -CH ₂ -CH ₂ - or -CH = CH-, and A - a group of the formula

means what R ^{6 - represents} hydrogen or alkyl, and R ^{7 - represents} hydrogen or - represents alkyl, aryl or aralkyl or - stands for a cation. 2. Disubstituted pyridines according to claim 1, of the formulas

in which R '- thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which up to 2 may be substituted in the same or different ways by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or - Phenyl or naphthyl means that up to 4 times the same or different substitution can be substituted by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl. Benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylthio, phenylethylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ , where R ⁴ and R ^{5 are} identical or different and are lower alkyl, phenyl, benzyl, acetyl, benzoyl, phenylsulfonyl or lower alkylsulfonyl, R ² denotes cyclopropyl, cyclopentyl or cyclohexyl, or - Lower alkyl means that can be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by a group of the formula -NR ⁴ R ⁵ , in which R ⁴ and R ^{5 have} the meaning given above, or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethylphenylylethylylphenylethylylphenylylethylphenylethylphenylethylphenylethylphenylethylphenylethylphenylethylphenylethylphenylethylphenylethylphenylethylphenyl The heteroaryl and aryl radicals mentioned can be substituted up to twice in the same or different manner by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy, R ^{3 -} hydrogen, or - Cyclopropyl, cyclopentyl or cyclohexyl, or - Lower alkyl means that can be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by a group of the formula - NRaRs, wherein R ⁵ and R ^{6 have} the meaning given above, or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylethsulfonyl, phenylethylphenyl, phenylethyl, phenylethylsulfonyl, phenylethoxy, phenylethoxy, The heteroaryl and aryl radicals mentioned can be substituted up to twice in the same or different manner by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy, - thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which up to 2-fold may be substituted identically or differently by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or - Phenyl or naphthyl means that up to 4 times the same or different substitution can be substituted by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl. Benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylthio, phenylethylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR ⁵ R ⁶ , where R ⁵ and R ^{6 have} the meaning given above, X is a group of the formula -CH = CH- and A - a group of the formula

means what R ^{6 represents} hydrogen or lower alkyl, and R ^{7 -} lower alkyl, phenyl or benzyl, or - means a physiologically compatible cation. 3. Disubstituted pyridines according to claims 1 and 2, wherein R 'is pyridyl, pyrimidyl, quinolyl or isoquinolyl, which can be substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or - Phenyl means that up to 3 times the same or different substitution can be substituted by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio , Ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, butoxycarbonyl, butoxy , R ² denotes cyclopropyl, cyclopentyl or cyclohexyl, or - Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, which can be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.butoxy, tert .Butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl, pyryl, pyridylylidyl, pyridylylidyl, pyridylyloxy, pyridylyl, pyridylyl, pyridylyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyryl, pyryl , Phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, R ^{3 is} hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or - Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl, which can be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tr.butylsulfoxy, methoxycarbonyl, methoxycarbonyl, methoxycarbonyl, methoxycarbonyl, methylbutylifoxyoxy, methoxycarbonyl, methylbutylifoxy, oxyoxyoxy , Isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, acetyl, ethylcarbonyl, or by a group -NR ⁴ _R ⁵ , where R4 and R ^{5 are the} same or different and are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, phenyl, benzyl, acetyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or phenylsulfonyl, or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, the heteroaryl and aryl radicals mentioned being fluorine, chlorine, methyl, ethyl, propyl Isopropyl, isobutyl, tert. Butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, trifluoromethyl or trifluoromethoxy may be substituted, or - Thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isooxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzothiazolyl, where the radicals mentioned are, by fluorine, by fluorine, Propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl. -Butoxycarbonyl may be substituted, or Phenyl means up to 3 times the same or different by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.Butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert.Butylsulfonyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyl, benzyloxy, benzylthio, Benzylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxycarbonyl, ethoxycarbonyi. Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl or can be substituted by a group -NR ⁴ R ⁵ , where R ⁴ and R ^{5 have} the meaning given above, X is a group of the formula -CH = CH- and A - a group of the formula

means what R ^{6 is} hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl and R ^{7 -} hydrogen. Means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl, or - means a sodium, potassium, calcium or magnesium or ammonium ion. 4. Disubstituted pyridines according to claims 1 to 3 for therapeutic treatment. 5. Process for the preparation of disubstituted pyridines of the formula

in which R '- Heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ may be substituted, wherein R ⁴ , R ^{S - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, Trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ , wherein R ⁴ and R ^{5 have} the meaning given above, R ² denotes cycloalkyl, or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁴ R ⁵ , in which R ⁴ , R ^{S - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl mean, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, the heteroaryl and aryl radicals of the latter substituents being different, up to 3 times identical, or up to 3 times identical Trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl can be substituted, R ^{3 represents} hydrogen, or cycloalkyl, or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula - _N R ⁴ _R ⁵ , in which R ⁴ , R ^{5 have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, the heteroaryl and aryl radicals being up to 3 times the same, or different, by halogenomethyloxy, trifluoromethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl, trifunctional or identical, Alkyl, alkoxy, alkylthio or alkylsulfonyl may be substituted, or -Heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ can be substituted, wherein R ⁴ and R ^{5 have} the meaning given above, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ , wherein R ⁴ and R ^{5 have} the meaning given above, X is a group of the formula -CH ₂ -CH ₂ - or -CH = CH-, and A - a group of the formula

means what R ^{6 - represents} hydrogen or alkyl, and R ^{7 - represents} hydrogen or - represents alkyl, aryl or aralkyl or - stands for a cation, characterized in that one Ketones of the general formula (VIII)

in which R ¹ , R ² and R ^{3 have} the meaning given above, and _R ^{s -} stands for alkyl, reduced, in the case of production of the acids, the esters are saponified, in the case of the production of the lactones, the carboxylic acids are cyclized, in the case of the preparation of the salts, either the esters or the lactones are saponified, in the case of the production of the ethylene compounds (X = -CH ₂ -CH ₂ -) the ethene compounds (X = -CH = CH-) are hydrogenated by customary methods, and optionally separates isomers. 6. The method according to claim 5, characterized in that one carries out the reduction in the temperature range from -80 ° C to + 30 C. 7. Ketones of the formula

in softer R '- heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, aikylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ may be substituted, wherein R °, R ^{5 - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or - Aryi means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ , wherein R ⁴ and R ^{5 have} the meaning given above, R ² denotes cycloalkyl, or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁴ R ⁵ , in which R ⁴ , R ^{S - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, the heteroaryl and aryl radicals of the latter substituents being up to 3 times the same, different by tri-fluoro, identical or different by Trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl can be substituted, R ^{3 represents} hydrogen, or - Cycloalkyl means or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁴ R ⁵ , in which R ⁴ , R ^{5 have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, wherein the heteroaryl and aryl groups of up to 3 times by identical or different halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl , Alkoxy, alkylthio or alkylsulfonyl may be substituted, or - Heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ can be substituted, wherein R ⁴ and R ^{5 have} the meaning given above, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ , wherein R ⁴ and R ^{5 have} the meaning given above, and _R ^{8 - represents} alkyl. 8. Process for the preparation of ketones of the formula

in which R '- Heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ may be substituted, wherein R ⁴ , R ^{S - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ , wherein R ⁴ and R ^{5 have} the meaning given above, R ² denotes cycloalkyl, or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁴ R ⁵ , in which R ⁴ , R ^{S - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, the heteroaryl and aryl radicals of the latter substituents being up to 3 times the same, different by tri-fluoro, identical or different by Trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl can be substituted, R ^{3 represents} hydrogen, or - Cycloalkyl means or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -N _R ⁴ _R 5, in which R ⁴ , R ^{5 have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, the heteroaryl and aryl radicals up to 3 times may be substituted, identically or differently, by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or - Heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ can be substituted, wherein R ⁴ and R ^{5 have} the meaning given above, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsuifamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ , wherein R ⁴ and R ^{5 have} the meaning given above, and R ⁸ - represents alkyl, characterized in that acididehydes of the general formula (IX)

in softer R ¹ , R ² and R ^{3 have} the meaning given above, in inert solvents with acetoacetic ester of the general formula (X)

in which R ^{8 has} the meaning given above, in the presence of bases. 9. The method according to claim 8, characterized in that one carries out the reaction in the temperature range from -80 C to + 50 ° C. 10. Medicament containing disubstituted pyridines according to claims 1 to 3. 11. Medicament according to claim 10, containing 0.5 to 98.5 wt .-% of disubstituted pyridines. 12. Use of disubstituted pyridines according to claims 1 to 3 for the treatment of diseases. 13. Use of disubstituted pyridines according to claims 1 to 3 for the manufacture of medicaments. 14. Use according to claim 13 for the manufacture of medicaments for the treatment of lipoproteinemia and arteriosclerosis.